4-(Tetrazol-5-yl)-Δ3 -cephem compounds

ABSTRACT

Certain novel antibacterial 7-acylamino-3-substituted-4-(tetrazol-5-yl)- DELTA 3-cephem derivatives, and salts thereof, and intermediates useful in their preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 508,634, filedSept. 23, 1974, now U.S. Pat. No. 3,966,719, which in turn is acontinuation-in-part of application Ser. No. 407,097, filed October 17,1973 and now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel antibacterial agents which are of valueas animal feed supplements, as therapeutic agents for the control ofinfectious diseases caused by gram-positive and gram-negative bacteria,and for the sterilization of hospital surfaces and the like; and tonovel intermediates for their production. More specifically, theantibacterial compounds of the instant invention are acylatedderivatives of 7-amino-3-substituted-Δ³ -cephem compounds which bear a5-tetrazolyl group at the 4-position.

2. Description of the Prior Art

In spite of the large number of cephem derivatives which have beenproposed for use as antibacterial agent, there still exists a need fornew agents.

The antibacterial compounds of this invention, and the intermediatesfrom which they are prepared by acylation, are all novel, and they arecompletely unanticipated in the prior art. U.S. Pat. Nos. 3,427,302 and3,468,874 disclose penam derivatives which incorporate a tetrazolylgroup as part of the 6-acylamino substituent, and Japanese PatentPublication No. 71-38503 discloses cephem derivatives which incorporatea tetrazolyl group as part of the 7-acylamino substituent. Cephemderivatives with a tetrazolylthiomethyl group at the 3-position are alsoknown (U.S. Pat. No. 3,641,021). However, the compounds of the instantinvention are unique in having a tetrazolyl group bonded directly to thecephem nucleus.

The biological and non-biological uses of tetrazoles has recently beenreviewed by Benson, "Heterocyclic Compounds," Elderfield, Ed., Vol. 8,John Wiley & Sons, Inc., New York, N. Y., 1967, Chapter 1, while acompilation of cephem references is noted in U.S. Pat. No. 3,766,176.

SUMMARY OF THE INVENTION

It has now been found that certain7-acylamino-3-substituted-4-(tetrazol-5-yl)-Δ³ -cephems and their saltsare useful as antibacterial agents, while certain 7-substitutedamino-3-substituted-4-carbamoyl- and 4-(tetrazol-5-yl)-Δ³ - and -Δ²-cephems are valuable intermediates leading to the preparation of theseantibiotics.

A preferred group of compounds useful as intermediates are those of theformula ##STR1## wherein R is hydrogen or an amino protecting moietyselected from the group consisting of 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl and ##STR2## where R₃,R₄ and R₅ are each hydrogen, chloro, bromo, fluoro, methyl, methoxy orphenyl; A is hydrogen, acetoxy, 1-methyltetrazolylthio or2-methyl-1,3,4-thiadiazolyl-5-thio; and R₂ is a potential tetrazoleprotecting moiety selected from the group consisting of ##STR3## whereR₆ is hydrogen, alkyl having from one to three carbon atoms or phenyl,R₇ is hydroxy, methoxy, alkanoyloxy having two to four carbon atoms orbenzyloxy and R₈ is hydrogen, hydroxy, fluoro, chloro, bromo, iodo,methyl, methoxy, alkanoyloxy having two to four carbon atoms, phenyl orbenzyloxy and ##STR4## where R₉ and R₁₀ are each hydrogen or methyl andX is oxygen or sulfur.

A second preferred class of compounds are intermediates of the formulae##STR5## and the salts thereof where R is hydrogen or an aminoprotecting group selected from the group consisting of2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,benzyloxycarbonyl and ##STR6## where R₃, R₄ and R₅ are each hydrogen,chloro, bromo, fluoro, methyl, methoxy or phenyl; A is hydrogen,acetoxy, 1-methyl-5-tetrazolylthio or2-methyl-1,3,4-thiadiazolyl-5-thio; R₁ is hydrogen, alkanoyloxymethylhaving from three to six carbon atoms, 1-(alkanoyloxy)ethyl having fromfour to seven carbon atoms, methoxymethyl or phthalidyl; and R₁₁ ishydrogen, alkanoyloxymethyl having from three to six carbon atoms,1-(alkanoyloxy)ethyl having from four to seven carbon atoms,methoxymethyl, phthalidyl or a potential tetrazole protecting moietyselecting from the group consisting of ##STR7## where R₆ is hydrogen,alkyl having from one to three carbon atoms or phenyl, R₇ is hydroxy,methoxy, alkanoyloxy having from two to four carbon atoms or benzyloxyand R₈ is hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyl,methoxy, alkanoyloxy having from two to four carbon atoms, phenyl orbenzyloxy and ##STR8## where R₉ and R₁₀ are each hydrogen or methyl andX is sulfur or oxygen.

A third class of preferred cephem derivatives and their salts are thoseof the formula ##STR9## where Ar is cyano, bromo, phenyl mono- ordisubstituted phenyl where each substituent is hydroxy, fluoro, chloro,bromo, amino, methoxy or methyl, phenoxy, phenylthio, pyridylthio,thienyl, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1-tetrazolyl; Q ishydrogen, hydroxy, azide, amino or carboxy; n is an integer of 0 or 1; Ais hydrogen, acetoxy, 1-methyltetrazol-5-ylthio or 2-methyl1,3,4-thiadiazol-5-ylthio; and R₁ is hydrogen, alkanoyloxymethyl havingfrom three to six carbon atoms, 1-(alkanoyloxy)ethyl having from four toseven carbon atoms, methoxymethyl or phthalidyl, provided that when Aris pyridylthio, phenoxy, phenylthio,2-methyl-1,3,4-thiadiazol-5-ylthiomethyl, cyano or bromo, and n is 1, Qis hydrogen or carboxy.

Also considered within the scope of the present invention are compoundsof the third preferred class wherein A, Q, n, and R₁ are as defined andAr is selected from the group consisting of hydrogen, alkyl having fromone to twelve carbon atoms, alkenyl having from two to twelve carbonatoms, cycloalkyl having from three to seven carbon atoms, cycloalkenylhaving from five to eight carbon atoms, cycloheptatrienyl,1,4-cyclohexadienyl, 1-aminocycloalkyl having from four to seven carbonatoms, 5-methyl-3-phenyl-4-isoxazolyl,5-methyl-3-(o-chlorophenyl)-4-isoxazolyl,5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolyl,5-methyl-3-(2-chloro-6-fluorophenyl)-4-isoxazolyl, 2-alkoxy-1-naphthylhaving from one to four carbon atoms in said alkoxy, sydnonyl, furyl,pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, triazolyl, imidazolyl,pyrazolyl, substituted phenoxy, substituted phenylthio, substitutedpyridylthio, substituted thienyl, substituted furyl, substitutedpyridyl, substituted tetrazolyl, substituted thiazolyl, substitutedisothiazolyl, substituted pyrimidinyl substituted triazolyl, substitutedimidazolyl and substituted pyrazolyl, each substituted moiety beingsubstituted by up to two members selected from the group consisting offluoro, chloro, bromo, hydroxy, hydroxymethyl, amino, N,N-dialkylaminohaving from one to four carbon atoms in each of said alkyl groups, alkylhaving from one to four carbon atoms, aminomethyl, aminoethyl, alkoxyhaving from one to four carbon atoms, alkylthio having from one to fourcarbon atoms, 2-aminoethoxy and N-alkylamino having from one to fourcarbon atoms.

As one skilled in the art can readily appreciate, the α-carbon atom ofthe antibacterial cephem side chain to which the amino or hydroxy, (Q)moiety is attached is an asymmetric carbon atom allowing for theexistence of two optically active isomers, the D- andL-diastereoisomers, as well as the racemate, DL, form. In accord withprevious findings concerning the activity of such cephems possessingasymmetric α-carbon atoms, the compounds of the present inventionpossessing the D-configuration are more active than those of theL-configuration and are the preferred compounds, although the L and DLforms of the instant compounds are also considered within the purview ofthe present invention.

Further, it is noteworthy to mention while considering asymmetriccenters, that there are several in the Δ³ -cephem nucleus, the basicbuilding block from which the compounds of the present invention arederived. These potential additional isomers are not significant in thisinstance since the 7-amino-Δ³ -cephem-4-carboxylic acid employed leadingto the products of this invention is that which is produced byfermentation and is consistently of one configuration.

In like manner, the term "tetrazole protecting group" or "tetrazolylcephem nitrogen protecting group" is intended to connote all groupsknown, or obvious, to one skilled in the art, which can be used (a) topermit the synthesis of the compounds wherein R is an amino protectinggroup and R² is the said tetrazolylcephem nitrogen protecting group, bythe process starting with 7-(protected amino)cephem-4-carboxylic aciddescribed hereinafter; and (b) can be removed from said compound whereinR² is the said tetrazolylcephem nitrogen protecting group, wherein R isselected from the group consisting of hydrogen and an amino protectinggroup, and R² is the said tetrazolylcephem nitrogen protecting group,using a method wherein the cephem ring system remains substantiallyintact. It is likewise the ability of the tetrazolylcephem nitrogenprotecting group to perform a specific function, to be discussed in moredetail hereinafter, rather than its precise chemical structure, which isimportant; and the novelty of the antibacterial agents of the inventiondoes not depend upon the structure of the protecting group. Selectionand identification of appropriate protecting groups can be made readilyand easily by one skilled in the art, and examples of several applicablegroups are given herein after.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to certain new and novel compositions of matterwhich are valuable as antibacterial agents, and as intermediates forpreparing said agents. For the sake of convenience, these compounds areidentified as derivatives of Δ³ -cephem. The term "Δ³ -cephem" has beendefined by Morin et al. in the Journal of the American Chemical Society,84, 3400 (1962) as meaning the structure ##STR10## Using thisterminology, the well-known antibiotic cephalosporin C, is designated as7-(5-amino-5-carboxyvaleramido)-3-acetoxymethyl-Δ³ -cephem-4-carboxylicacid.

Many of the compounds of this invention are also 5-substitutedtetrazoles which can exist in two isomeric forms, viz: ##STR11##

As will be appreciated by one skilled in the art, when the substituentrepresented by L is hydrogen, the two forms co-exist in a dynamictautomeric, equilibrium mixture. However, in the case where L representsa substituent other than hydrogen, the two forms represent differentchemical structures which do not spontaneously interconvert.

In accordance with the process employed for synthesizing the cephemintermediates and antibacterial agents of the present invention, twopreparative routes are amenable. The first is illustrated as follows:##STR12## wherein R, A, R₂, Ar, n and Q are as previously defined and R₁and R₁₁ are each hydrogen.

Experimentally, 7 -carboxamido-3-substituted-Δ³ -cephem-4-carboxylicacids (1), prepared by acylation of the corresponding 7-amino-cephem,are converted to the 4-carbamoyl compounds (2) by reacting the 4-carboxymoiety, activated as the 2,4-dinitrophenol ester, with an appropriateamine, R₂ NH₂.

Preparation of compounds (2), wherein R is derived from triphenylmethyl,is achieved either by alkylation of the 7-amino compound; followed byformation of the 4-carbamoyl group as mentioned above, or by selectivelyremoving the R acyl group of compounds of structure (2), such asremoving the 2,2,2-trihaloethoxycarbonyl group using acetic acid andzinc dust, and subsequently alkylating the 7-amino-4-carbamoylcephemcompound with the requisite triphenylmethyl chloride.

The reaction of (2) to (3) requires conversion of the 4-carbamoyl moietyof (2) to the appropriate imino chloride followed by reaction of thissubstrate with azide. Formation of the imino chloride is mostconveniently carried out using phosgene, or phosphorous pentachloride ina reaction inert solvent such as chloroform, while reaction of the iminochloride with the salt of hydrazoic acid and tetramethylguanidine leadsto the formation of the tetrazole ring. As one skilled in the art caneadily appreciate, there are many sources of azide which could also beemployed in this reaction including salts of hydrazoic acid withinorganic bases, such as sodium azide, lithium azide, potassium azideand ammonium azide. Because of the explosive nature of many metal azidesit is advantageous, and in this case preferred, that azides formed fromorganic bases be employed; tetramethylguanidine hydrogen azide isparticularly suited for this purpose.

The sequential step for conversion of (3) to (4) requires the removal ofthe "amino protecting group," R. The reaction conditions employed toaffect this removal are dictated by the nature of the group to beremoved. As previously mentioned, the 2,2,2-trihaloethoxycarbonyl moietyis conveniently removed using zinc dust and acetic acid; thetriphenylmethyl group is removed using formic acid; and thebenzoxycarbonyl moiety is removed by treating (3) with a mixture oftrifluoroacetic acid/anisole (4:1; v/v) and trifluoromethylsulfonicacid. It is preferred, in this last mentioned procedure that thereaction be conducted at ice-bath temperatures (0° C.) and for a limitedperiod of time, usually for 4-6 minutes. If higher temperatures areemployed, such as 25°-40° C. temperature, or longer reaction times, suchas 1-3 hrs. it is possible to remove the "tetrazole blocking" groupsimultaneously.

Following removal of the "amino protecting" moiety, the R₂ variable isremoved by treatment of (4) or the p-toluene sulfonic acid salt thereofwith the aforementioned mixture of trifluoroacetic acid/anisole.

Acylation of (5) with the appropriate carboxylic acid activated eitheras an acid halide, activated ester, mixed anhydride or the acid with acarbodiimide provides for the preparation of the antibacterial compoundsof the present invention.

As one skilled in the art can readily appreciate, the presence of otherfunctional groups in the acylating acid may require that said groups bemasked to prevent them from undergoing competing reactions. When theacylation is complete the groups can be unmasked.

For examples, in preparing compounds of structure (6) wherein Q isamino, it is required that said amino group be blocked, preferrably witha t-butoxy carbonyl group, the blocking group being removed by acidtreatment after the acylation is complete. A similar practice isrequired wherein Q is hydroxy, in which case a formyl group is employedto mask the hydroxy group.

Compounds of structure (6) wherein Ar is bromo, n is 1 and Q ishydrogen, in addition to having antibacterial activity can be reactedwith mercaptans leading to still additional antibacterial compounds.

The starting materials for the sequence of reactions are either readilyavailable as commercial reagents or can be prepared by literatureprocedures. For example, the 7-amino-3-substituted-Δ³-cephem-4-carboxylic acids are reported in U.S. Pat. No. 3,641,021; theamines R₂ NH₂ are conveniently prepared by one or more procedures astaught by Wagner and Zook, "Synthetic Organic Chemistry," John Wiley andSons, Inc., New York, N.Y., 1956, Chapter 24, p. 653-727; while thetriphenylmethyl chlorides employed are prepared by the procedure astaught by Bachmann, Org. Synthesis, 23, 100 (1943).

The second procedure suitable for the synthesis of the antibacterialcompounds of the present invention and the intermediates in thepreparation thereof is illustrated as follows: ##STR13## wherein R, A,R₂, Ar, n and Q are as previously indicated and R₁ is methoxymethyl.

In practice, the 7-acylamino-3-methyl-Δ³ -cephem-4-carboxylic acid (1)is isomerized to the corresponding 7-acylamino-3-methyl-Δ²-cephem-4-carboxylic acid (7), allowing for the activation of the3-methyl in subsequent reactions.

Preparation of the 4-carbamoyl group in compounds of structure (8) iscarried out by procedures similar to those in the first syntheticsequence previously discussed.

Further, in a manner analogous to the first sequence, compound (8) aretransformed into tetrazoles of structure (9) by the same proceduresinvolving formation of the imino chloride and its subsequent interactionwith azide.

Removal of the "tetrazole protecting" group of compounds 9 leading to(10) is affected in the manner previously discussed in the firstsynthetic route and comprises contacting (9) with trifluoroaceticacid/anisole at 30°-50° C. for several hours.

Prior to bromination of the activated 3-methyl substituent the tetrazoleof (10) is blocked by alkylation with chloromethyl methyl ether. As oneskilled in the art will appreciate, alkylation can, and does, take placeat both the N₁ and N₂ position, with alkylation predominating at N₂.Since the blocking group is removed in a later step of the sequence itis practical that the two isomers not be separated subsequent to thealkylation. Further, both isomers serve the same purpose and are equallyuseful in this regard.

The 3-methyl substituent of (11) is brominated with N-bromosuccinimidein the presence of a peroxide, a well known type of brominationprocedure. Following the completion of the bromination, the3-bromomethyl compound is not isolated but allowed to react with aparticular nucleophilic reagent such as a mercaptan or an acetate saltgiving (12).

Removal of the "amino protecting" group of (12) is carried out bymethods previously discussed in the first synthetic sequence.

Similarly, acylation of (13) is affected using the aforementionedprocedures, with the same consideration being given to the protection or"masking" of any functional group on the acylating acid which maycompete in the acylation reaction with the 7-amino group of the Δ²-cephem (13).

Reisomerization of the Δ² bond of (14) to the Δ³ position is achieved byoxidation of the sulfur atom of the cephem molecule with a per acid suchas n-chloroperbenzoic acid giving (15). Treatment of (15) with stannouschloride and acetyl chloride results in the formation of the desired Δ³-Cephem of structure (16).

The N₁ and N₂ blocking groups are removed from (16) usingtrifluoroacetic acid/anisole as previously discussed and "masking"groups are removed from the acyl moiety of the 7-acylamino group if theyare present.

A modification of the second reaction sequence allows for thepreparation of compounds wherein R₁ is derived from phthalidyl, or analkanoyloxymethyl or 1-(alkanoyloxy)ethyl moiety. The procedure leadingto the preparation of these compounds utilizes the alkylation of thetetrazole moiety of (10) with an appropriate alkanoyloxymethyl halide or1-(alkanoyloxy)ethyl halide (Ulich, et al, J. Am. Chem. Soc., 43,660(1921) and Euranto, et al. Acta. Chem. Scand., 20, 1273 (1966) orphthalidyl halide in place of chloromethyl methyl ether. The phthalidyl,alkanoyloxymethyl and 1-(alkanoyloxy)ethyl substituted tetrazoles of thefinal products are pro-drug forms of the final products, and althoughinactive or of relatively low activity against micro organisms per seare metabolized to the free tetrazole (R₁ ═H) when injected parenterallyinto the animal, including man. The rate of metabolic conversion ofthese compounds to the free tetrazole occurs at such a rate as toprovide an effective and prolonged concentration of the free tetrazolein the animal body. In effect, such compounds act as depot sources forthe free tetrazole antibacterial agent. Regarding the antibacterialactivity of these pro-drug forms, both the N₁ and the N₂ substitutedisomers possess activity and usefulness.

If phthalidyl, alkanoyloxymethyl or 1-(alkanoyloxy)ethyl, N₁ /N₂substituted tetrazoles are to be synthesized by the second syntheticroute, the reaction step (16→6) is omitted, and only the masking groupsare removed from the acyl portion of the side chain.

Alternate methods exists for the synthesis of those antibacterialproducts bearing a phthalidyl, alkanoyloxymethyl or 1-(alkanoyloxy)ethylgroup at the N₁ /N₂ position of the tetrazole moiety. One methodembraces alkylation of the base salt of an appropriate7-amino-3-substituted-4-(tetrazole-5-yl)-Δ³ -cephem followed byacylation of the 7-amino group as previously discussed. The secondmethod utilizes alkylation of the base salt of an appropriate7-acyl-amino-3-substituted-4-(tetrazol-5-yl)-Δ³ -cephem; both methodsincluding the removal of "masking" groups from the side chain, ifnecessary.

Regarding this second series of reactions leading to the intermediatesand final product of the present invention, the preferred"aminoblocking" groups are the 2,2,2-trihaloethoxycarbonyl moieties.

As has been previously noted, a characteristic feature of the acidiccompounds of the instant invention, those wherein R₁ or R₁₁ are H or Qis carboxy, is their ability to form basic salts. Acid congeners of thepresent invention are converted to basic salts by the interaction ofsaid acid with an appropriate base in an aqueous or nonaqueous medium.Such basic reagents suitably employed in the preparation of said saltscan vary in nature, and are meant to contemplate such bases as organicamines, ammonia, alkali metal hydroxides, carbonates, bicarbonates,hydrides and alkoxides, as well as alkali earth metal hydroxides,hydrides, alkoxides and carbonates. Representative of such bases areammonia, primary amines such as n-propylamine, n-butylamine, aniline,cyclohexylamine, benzylamine, p-toluidine, ethylamine, octylamine,secondary amines such as dicyclohexylamine and tertiary amines such asdiethylaniline, N-methylpyrrolidine, N-methylmorpholine and1,5-diazabicyclo-[4,3,0]-5-nonene; sodium hydroxide, potassiumhydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide,magnesium hydroxide, calcium hydride and barium hydroxide.

As one skilled in the art can readily appreciate, some compounds of theinstant invention are sufficiently basic, by virtue of those finalproducts wherein Q is amino, to form acid addition salts; said salts,especially the pharmaceutically acceptable acid addition salts, are alsoconsidered within the scope of this invention.

In addition, those useful intermediates of the present invention whichcontain a free 7-amino moiety or a free tetrazole (R₁, R₁₁ ═H) are alsocapable of forming acid addition salts and base salts, respectively.These salts are useful either in the characterization of theseintermediates, such as the acid addition salts, or are utilized inreactions, such as alkylation of the base salt of the tetrazoles.

In utilization of the chemotherapeutic activity of those compounds ofthe present invention which form basic salts, it is preferred, ofcourse, to use pharmaceutically acceptable salts. Although waterinsolubility, high toxicity, or lack of crystalline nature may make somesalt species unsuitable or less desirable for use as such in a givenpharmaceutical application, the water insoluble or toxic salts can beconverted to the corresponding acids by decomposition of the salts, oralternately they can be converted to any desired pharmaceuticallyacceptable basic salt. The said pharmaceutically acceptable saltspreferred include the sodium, aluminum, potassium, calcium, magnesium,ammonium, and substituted ammonium salts, e.g., procaine, dibenzylamine,N,N-bis(dehydroabietyl)ethylenediamine, 1-ephenamine, N-ethylpiperidine,N-benzyl-β-phenethylamine, N,N'-dibenzylethylenediamine, triethylamine,as well as salts with other amines which have been used to form saltswith cephems.

The novel cephems described herein exhibit in vitro activity against avariety of micro-organisms, including both gram-positive andgram-negative bacteria. Their useful activity can readily bedemonstrated by in vitro tests against various organisms in abrain-heart infusion medium by the usual two-fold serial dilutiontechnique. The in vitro activity of the herein described compoundsrenders them useful for topical application in the form of ointments,creams, and the like, or for sterilization purposes, e.g., sick-roomutensils.

These novel cephems are also effective antibacterial agents in vivo inanimals, including man, not only via the parenteral route ofadministration but also by the oral route of administration.

Obviously, the physician will utimately determine the dosage which willbe most suitable for a particular individual person, and it will varywith the age, weight, and response of the particular patient as well aswith the nature and extent of the symptoms, the nature of the bacterialinfection being treated and the pharmacodynamic characteristics of theparticular agent to be administered. It will often be found that whenthe composition is administered orally, larger quantities of the activeingredient will be required to produce the same level as produced by asmaller quantity administered parenterally.

Having full regard for the foregoing factors it is considered that aneffective daily oral dose of the compounds of the present invention inhumans of approximately 50-1000 mg./kg. per day, with a preferred rangeof about 250-750 mg./kg. per day in single or divided doses, and aparenteral dose of 25-500 mg./kg. per day, with a preferred range ofabout 125-400 mg./kg. per day will effectively alleviate the symptoms ofthe infection. These values are illustrative, and there may, of course,be individual cases where higher or lower dose ranges are merited.

The preferred compounds of the present invention which are useful asintermediates are7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³^(') -cephem, 7-(benzyloxycarboxamido)-3-methyl-[N-(p-methoxybenzyl)carbamoyl]-Δ³ -cephem,7-(N-triphenylmethylamino)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-.DELTA.³-cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem,7-(benzyloxycarboxamido)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem,7-(N-triphenylmethylamino)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ²-cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem,7-(N-triphenylamino)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem, 7-amino-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem,7-benzyloxycarboxamido)-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³ -cephem,7-amino-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³ -cephem,7-(benzyloxycarboxamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem,7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ²-cephem,7-(benzyloxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem, 7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,7-amino-3-acetoxymethyl-4-(tetrazol-5-yl)-Δ³ -cephem,7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-.DELTA.³-cephem,7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ.sup.3-cephem, 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-Δ² -cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1-(methoxymethyl)tetrazol-5-yl]-Δ² -cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[2-(methoxymethyl)tetrazol-5-yl]-Δ²-cephem,

7-amino-3-methyl-4-[1-(methoxymethyl)tetrazol-5-yl]-Δ² -cephem,7-amino-3-methyl-4-[2-(methoxymethyl)tetrazol-5-yl]-Δ² -cephem,7-amino-3-acetoxymethyl-4-[1-(methoxymethyl)tetrazol-5-yl]-Δ² -cephem,7-amino-3-acetoxymethyl-4-[1-(methoxymethyl)tetrazol-5-yl]-Δ² -cephem,7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-[1-(methoxymethyl)tetrazol-5-yl]-Δ²-cephem,7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-[2-(methoxymethyl)tetrazol-5-yl]-Δ²-cephem,7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-methoxymethyl)tetrazol-5-yl]-Δ²-cephem,7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[2-(methoxymethyl)tetrazol-5-yl]-Δ²-cephem,7-(2',2',2'-trichloroethoxycarboxamido)-3-bromomethyl)-4-[1-methoxymethyl)tetrazol-5-yl]-Δ²-cephem and7-(2',2',2'-trichloroethoxycarboxamido)-3-bromomethyl-4-[2-(methoxymethyl)tetrazol-5-yl]-Δ²-cephem.

The preferred antibacterial agents of the present invention are7-phenylacetamido-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,7-phenoxyacetamido-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,7-(2-thienylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,7-phenylacetamido-3-methyl-4-[2-(pivaloyloxymethyl)tetrazol-5-yl]-Δ.sup.3-cephem,7-phenoxyacetamido-3-methyl-4-[2-(pivaloyloxymethyl)tetrazol-5-yl]-Δ³-cephem and7-(2-thienylacetamido)-3-methyl-4-[2-(pivaloyoxymethyl)tetrazol-5-yl]-Δ³ -cephem.

The antimicrobial data of a number of compounds of the instant inventionagainst Streptomyces pyogenes are provided in the following table. Thetests were run under standardized conditions in which nutrient brothcontaining various concentrations of the test material was seeded withthe particular organism specified, and the minimum concentration (MIC)at which growth of each organism failed to occur was observed andrecorded.

                  TABLE I                                                         ______________________________________                                         ##STR14##                                                                                                In vitro                                          R.sup.1         A           MIC (mcg./ml.)                                    ______________________________________                                        C.sub.6 H.sub.5 CH.sub.2                                                                      H           0.78                                              C.sub.6 H.sub.5 OCH.sub.2                                                                     H           3.1                                                ##STR15##       H           0.4                                               ##STR16##      H           6.2                                                ##STR17##      H           1.5                                                ##STR18##      H           1.5                                                ##STR19##      H           1.5                                                ##STR20##      H           0.78                                               ##STR21##                                                                                     ##STR22##  3.12                                               ##STR23##       OCOCH.sub.3                                                                               1.6                                               ##STR24##                                                                                     ##STR25##  0.1                                               ______________________________________                                    

The novel antibacterial agents of the present invention are remarkablyeffective in treating a number of infections caused by susceptiblegram-negative and gram-positive bacteria in poultry and animalsincluding man. For such purposes, the pure materials or mixtures thereofwith other antibiotics can be employed. They may be administered aloneor in combination with a pharmaceutical carrier on the basis of thechosen route of administration and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tabletscontaining such excipients as starch, milk sugar, certain types of clay,etc., or in capsules alone or in admixture with the same or equivalentexcipients. They may also be administered orally in the form of elixirsor orall suspensions which may contain flavoring or coloring agents, orbe injected parenterally, that is, intramuscularly or subcutaneously.For parenteral administration, they are best used in the form of asterile aqueous solution which may be either aqueous such as water,isotonic saline, isotonic dextrose, Ringer's solution, or non-aqueoussuch as fatty oils of vegetable origin (cotton seed, peanut oil, corn,sesame) and other non-aqueous vehicles which will not interfere with thetherapeutic efficiency of the preparation and are nontoxic in the volumeor proportion used (glycerol, propylene glycol, sorbitol). Additionally,compositions suitable for extemporaneous preparation of solutions priorto administration may advantageously be made. Such compositions mayinclude liquid diluents, for example, propylene glycol, diethylcarbonate, glycerol, sorbitol, etc.; buffering agents, as well as localanesthetics and inorganic salts to afford desirable pharmacologicalproperties.

The following examples are provided solely for the purpose of furtherillustration. Infrared (IR) spectra are measured as potassium bromidediscs (KBr discs) or as Nujol mulls, and diagnostic absorption bands arereported in wave numbers (cm.sup.⁻¹). Nuclear magnetic resonance spectra(NMR) are measured at 60 MHz for solutions in deuterochloroform (CDCl₃),perdeutero dimethyl sulfoxide (DMSO-d₆) or deuterium oxide (D₂ O), andpeak positions are expressed in parts per million (ppm) downfield fromtetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. Thefollowing abbreviations for peak shapes are used: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet.

EXAMPLE 17-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem

A. 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-Δ³-cephem-4-carboxylic acid

To a suspension of 555 g. of 7-amino-3-methyl-Δ³ -cephem-4-carboxylicacid in 16.65 l. of 1:2 acetone/water solution is added 600 g. of sodiumbicarbonate and the mixture allowed to stir at room temperature for 30min. To the resulting solution is added, over a 45 min. period, 600 g.of 2,2,2-trichloroethoxycarbonyl chloride, and the reaction mixtureallowed to stir for an additional 18 hrs. The mixture is extracted withmethylene chloride and the aqueous layer separated and acidified to pH 2with 5N hydrochloric acid. The acidified aqueous is extracted with freshmethylene chloride (3 × 1.5 l. and 2 × 500 ml.) and the combined organiclayers washed successively with 5N hydrochloric acid (2 × 500 ml.) andwater (3 × 500 ml.), and dried over magnesium sulfate. The thick oil,which remains after the solvent is removed in vacuo, is dissolved in 2l. of diethyl ether and added dropwise to 1.5 l. of petroleum ether. Theintermediate product slowly crystallizes from solution (70% yield).

NMR (DMSOd₆): δ = 5.4 (q) 1H; 5.1 (d) 1H; 4.85 (s) 1H; 3.42 (s) 2H; 2.0(s) 3H.

IR (KBr disc) γ max: 1770 cm.sup.⁻¹ (β-lactam carbonyl).

The product is stored in a dioxane solution for use in subsequentreactions without further purification.

B.7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoyl]-Δ³-cephem.

A solution containing 1.84 g. of 2,4-dinitrophenol in 35 ml. ofmethylene chloride is treated with 4 g. of7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-Δ³ -cephem-4-carboxylicacid in a minimum amount of dioxane followed by a solution of 2.1 g. ofdicyclohexyl carbodiimide in 20 ml. of methylene chloride. Afterallowing the reaction mixture to stir for 30 min. at room temperature,the dicyclohexyl urea is filtered, washed with methylene chloride, andthe filtrate and washings combined and treated with 1.4 g. ofp-methoxybenzylamine in 14 ml. of methylene chloride.

After 30 min. at room temperature, the reaction mixture is washed with asaturated sodium carbonate solution and the organic phase dried overmagnesium sulfate. The thick oil, which remains after the solvent isremoved under reduced pressure, is triturated with petroleum ether. Thecrystallized product is filtered and dried to give 4.0 g. of a paleyellow solid.

NMR (DMSOd₆): δ = 8.5 (t) 1H; 7.0 (q) 4H; 5.3 (q) and 4.95 (d) 2H; 4.8(s) 2H; 4.3 (d) 2H; 3.7 (s) 3H; 3.45 (broad) 2H and 2 (s) 3H.

IR (KBr disc) γ: 1770 cm.sup.⁻¹ (β-lactam carbonyl).

EXAMPLE 2

Starting with the appropriate amine and requisite 7-amino-3-methyl-Δ³-cephem-4-carboxylic acid, and utilizing the procedure of Example 1, thefollowing 7-acylamino-3-methyl-4-(N-substitutedcarbamoyl)-Δ³ -cephemsare synthesized:

    ______________________________________                                         ##STR26##                                                                    R                    R.sub.2                                                  ______________________________________                                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O 3-FC.sub.6 H.sub.3 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Cl.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                          Cl.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Cl.sub. 3 CCH.sub.2 OCO                                                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)              Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(φ)                                  Cl.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2                      H.sub.5)                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Cl.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl                                                Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-thienylmethyl-                                      Cl.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Cl.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Br.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub. 6 H.sub.4 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2               Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Br.sub.3 CCH.sub.2 OCO                                                                       2-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Br.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Br.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Br.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Br.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     ______________________________________                                    

EXAMPLE 37-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[1-p-methoxybenzyltetrazol-5-yl]-Δ³-cephem

To a suspension of 100 g. of7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem in 2 l. of chloroform is added dropwise 250 ml. of toluenecontaining 30 g. of phosgene over a 15 min. period. After a further 15min. a solution of 24 g. of dry pyridine in 100 ml. of chloroform isadded dropwise over 45 min., during which a solution is effected andcarbon dioxide is slowly evolved. The solution is stirred for 90 min.,and is subsequently concentrated to half volume in vacuo to remove theexcess phosgene. Chloroform (2 l.) is added, and to this stirredsolution is then added 45 g. of tetramethyl guanidinium azide in 250 ml.of chloroform. After 2 hrs., the chloroform solution is washedsuccessively with water (2 × 500 ml.), saturated sodium carbonatesolution (2 × 300 ml.), 2.5N hydrochloric acid and water (1 × 250 ml.).The organic phase is dried over magnesium sulfate and concentrated invacuo to a gummy solid, 102 g. The product is further purified bychromatographing on a column of alumina (306 g.) using chloroform as thesolvent (408 ml.) and eluate (1.5 l.). The eluate is added with stirringto 6 l. of petroleum ether, resulting in the precipitation of theproduct as a light brown solid, 79 g.

NMR (CDCl₃): δ = 6.9 (q) 4H; 5.4 (m) 3H; 4.9 (d) 1H; 4.7 (s) 2H; 3.7 (s)3H; 3.3 (q) 3H and 1.4 (s) 3H.

IR (KBr disc) γ: 1770 cm.sup.⁻¹ (β-lactam carbonyl).

In a similar manner, 250 mg. of7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem, 0.007 ml. of pyridine and 2.6 mg. of phosphorous pentachloridein 6 ml. of chloroform yield the corresponding imino chloride, which ontreatment with tetramethyl guanidinium azide (1 g.) in 2 ml. ofchloroform gave 220 mg. of the desired tetrazole, identical in allrespects with that obtained above.

EXAMPLE 4

Utilizing the intermediate amides of Example 2, and employing theprocedure of Example 3, the following tetrazole derivatives aresynthesized:

    ______________________________________                                         ##STR27##                                                                    R                    R.sub.11                                                 ______________________________________                                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O 3-FC.sub.6 H.sub.3 CH.sub.3       Cl.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Cl.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                          Cl.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub. 6 H.sub.3 CH(CH.sub.3)           Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)              Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(φ)                                  Cl.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub. 2 OCO                                                                      3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2                      H.sub.5)                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Cl.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Cl.sub. 3 CCH.sub.2 OCO                                                                      5-methyl-2-thienylmethyl-                                      Cl.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Cl.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Br.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2               Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Br.sub.3 CCH.sub.2 OCO                                                                       2-F4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Br.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Br.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Br.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Br.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     ______________________________________                                    

EXAMPLE 5 7-Amino-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem

To 73 g. of7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem in 500 ml. of 95% acetic acid is added 25 g. of zinc dust, andthe mixture stirred vigorously for 3 hrs. at room temperature. Themixture is filtered, and the filtrate added to a large volume of waterand extracted with chloroform. The organic layer is washed with waterand the product extracted from the organic phase with 1N hydrochloricacid. The aqueous is washed with chloroform, basified with 2N sodiumhydroxide solution to pH 7 and extracted with chloroform. The chloroformlayer is dried over magnesium sulfate and concentrated under reducedpressure to a small volume. On addition of the concentrate to petroleumether, the product is precipitated. The solids are filtered and dried,30 g.

NMR (DMSOd₆): δ = 7(2 q) 8H; 5.5(s) 2H; 5.4(d) 1H; 5.05(d) 1H; 3.7(s)3H; 3.6(s) 2H; 2.2(s) 3H and 1.4(s) 3H.

EXAMPLE 6

Starting with the intermediate tetrazoles of Example 4, and repeatingthe procedure of Example 5, the following congeners are synthesized:

    ______________________________________                                         ##STR28##                                                                               R.sub.11                                                           ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub. 5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                     3-Cl4-C.sub.6 H.sub.4 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl- 5-methyl-2-furylmethyl- -2-thienylmethyl-                      5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 7 7-Amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem

A mixture of 7.0 g. of7-amino-3-methyl-4-(1-[p-methoxybenzyl]-tetrazol-5-yl)-Δ³ -cephemin 50ml. of trifluoroacetic acid/anisole (4:1) is allowed to stand at 50° C.for 5 hrs. The solution is subsequently poured into a large volume ofstirred diethyl ether, and the precipitate which forms is filtered. Thesolids are dissolved in water, which is extracted several times withethyl acetate, adjusted to pH 7.0 with 2N aqueous sodium hydroxide andextracted again. The aqueous solution containing the product is freezedried to give 3.2 g. of the desired compound (containing some sodiumtrifluoroacetate).

NMR (DMSOd₆): δ = 5.0(d) 1H; 4.6(d) 1H; 3.4(q) 2H; 1.9(s) 3H and 1.3(s)3H.

EXAMPLE 8

In an analogous manner, when the procedure of Example 7 is repeated,starting with the compounds of Example 6,7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem is produced.

EXAMPLE 9 7-Benzyloxycarboxamido)-3-methyl-Δ³ -cephem-4-carboxylic Acid

Sodium bicarbonate (500 g.) is added portionwise over 45 min. to astirred slurry of 7-amino-3-methyl-Δ³ -cephem-4-carboxylic acid (560 g.)in cold water (5.6 liters) and acetone (5.6 liters). When effervescencehas ceased, benzyl chloroformate (490 g.) is added and the solutionstirred at room temperature overnight. The reaction mixture is thenextracted with ethyl acetate (2 × 1 liter), and the pH of the separatedaqueous layer adjusted to 2 by the addition of 2N hydrochloric acid.This mixture is then extracted with ethyl acetate (2 × 1 liter), and thesolvent from the separated organic layer removed in vacuo. The resultantsolid is dissolved in hot ethanol (2 liters), and diluted with warmwater (5 liters), to furnish 7-(benzyloxycarboxamido)-3-methyl-Δ³-cephem-4-carboxylic acid as a white solid (750 g.), which is dried invacuo at 60° C.

NMR (DMSOd₆): δ = 8.3(d) 1H; 7.3(m) 5H; 5.4(q) 1H; 5.1(d) 1H; 5(s) 2H;3.4(q) 2H and 2.1(s) 3H.

EXAMPLE 10

Utilizing the procedure of Example 9, but starting with a suitably ringsubstituted benzyl chloroformate wherein the substituent is selectedfrom the group consisting of halo, methyl and methoxy, the corresponding7-(substituted benzyloxycarboxamido)-3-methyl-Δ³ -cephem-4-carboxylicacids are prepared.

EXAMPLE 117-(Benzyloxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoyl]-Δ³-cephem

A mixture of 7-(benzyloxycarboxamido)-3-methyl-Δ³ -cephem-4-carboxylicacid (34.8 g.) and 2,4-dinitrophenol (18.4 g.) are dissolved in drydioxane (700 ml.). Dicyclohexylcarbodiimide (20.6 g.) is then added andthe solution stirred for 20 min. at room temperature. After this time,the precipitated dicyclohexylurea is filtered off, and the filtratetreated with p-methoxybenzylamine (13.7 g.) which is added over 10 min.After a further 15 min., the reaction mixture is diluted with dry ether(1.4 liters). The precipitate is filtered off, washed with dry ether(500 ml.), and dried in vacuo at 50° C. to yield 40 g. of the desiredproduct as a white solid.

NMR (DMROd₆): δ = 8.4(m) 2H; 7(q) 4H; 5.3(q) 1H; 5.1(s) 2H; 5(d) 1H;4.3(d) 2H; 3.7(s) 3H; 3.3(s) 2H and 2(s) 3H.

EXAMPLE 12

Starting with the appropriate amine and requisite7-(benzyloxycarboxamido)-3-methyl-Δ³ -cephem-4-carboxylic acid andemploying the procedure of Example 11, the following Δ³ -cephems areprepared:

    ______________________________________                                         ##STR29##                                                                               R.sub.2                                                            ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CF.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.4 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 13 7-Amino-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³ -cephem

7-(Benzyloxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ.sup.3-cephem (20 g.) is dissolved in hydrobromic acid/acetic acid (200 ml.)and the solution stirred at room temperature until gas evolution ceases.The mixture is poured into a large volume (ca. 2 liters) of stirredether and the resulting precipitate collected. The solid is dissolved inwater and the aqueous solution washed with ethyl acetate (2x). Theaqueous solution is adjusted to pH 7.5 with sodium bicarbonate and thesuspension extracted with chloroform. The chloroform extract is dried(MgSO₄) and evaporated under reduced pressure to leave the product as apale yellow solid (7.7 g.).

NMR (DMSOd₆): δ = 8.0(t) 1H; 7.0(q) 4H; 4.8(d) 1H; 4.6(d) 1H; 4.4(d) 2H;3.7(s) 3H; 3.2(q) 2H; 2.1(s) 2H and 2.0(s) 3H.

EXAMPLE 14

Starting with the intermediates of Example 12, and following thedeacylation procedure of Example 13, the following 7-amino-Δ³ -cephemderivatives are synthesized:

    ______________________________________                                         ##STR30##                                                                               R.sub.2                                                            ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CF.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-FCH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                         3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.4 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 157-(N-Triphenylmethylamino)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoyl]-.DELTA.³-cephem

To 24 g. of 7-amino-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³ -cephemin chloroform (ethanol free; 300 ml.) is added triphenylmethyl chloride(21.0 g.) and triethylamine (7.64 g.). The mixture is allowed to standat room temperature in the absence of light for 15 hrs. The solution isthen diluted several-fold with chloroform and washed twice with water.The organic solution is dried (MgSO₄) and evaporated to dryness to leavethe required product as a foam. Trituration with light petroleum ethergives a pale yellow solid (40 g.).

NMR (CDCl₃): δ = 7.2, 9H; 4.6(q) 1H; 4.4(d) 2H; 4.1(d) 1H; 3.7(s) 3H;3.0, 3H and 2.0(s) 3H.

EXAMPLE 16

The procedure of Example 15 is repeated, substituting the 7-amino-Δ³cephems of Example 14 for7-amino-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³ -cephem, to providethe following compounds:

    ______________________________________                                         ##STR31##                                                                               R.sub.2                                                            ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I 4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CF.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.4 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 17

The procedure of Example 15 is again repeated, starting with theappropriate triphenylmethyl chloride and 7-amino-Δ³ -cephem from Example14 to give the following compounds:

    __________________________________________________________________________     ##STR32##                                                                    R.sub.3                                                                              R.sub.4                                                                              R.sub.5    R.sub.2                                              __________________________________________________________________________    H      H      4-CH.sub.3                                                                           4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          1                                                        H      H      2-CH.sub.3                                                                           4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3                                CH.sub.2                                                 H      H      3-CH.sub.3 O                                                                         2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 H      H      4-CH.sub.3 O                                                                         3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                         H      H      2-F    3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2          H      H      4-F    4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                         H      H      3-Cl   2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 H      H      4-Cl   4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                    H      H      4-Br   2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)      H      4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)        H      4-CH.sub.3                                                                           4-CH.sub.3                                                                           3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2           H      4-CH.sub.3                                                                           4-CH.sub.3 O                                                                         4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2      H      4-CH.sub.3 O                                                                         4-CH.sub.3 O                                                                         3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2          H      3-CH.sub.3 O                                                                         3-F    4-HOC.sub.6 H.sub.4 CH(φ)                            H      3-CH.sub.3 O                                                                         4-F    3-I4-CH.sub.3 OC.sub.6 H.sub.3 C.sub.2                   H      3-CH.sub.3 O                                                                         4-F    4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH.sub.2                                                 H      4-Cl   3-Cl   3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub. 2 C.sub.6                               H.sub.3 CH.sub.2                                         H      4-Cl   4-F    4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                 H      4-Cl   4-Br   4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)          H      4-Br   4-Br   3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                  H      3-Br   4-CH.sub.3 O                                                                         3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)             H      4-Br   4-CH.sub.3                                                                           4-HOC.sub.6 H.sub.4 CH.sub.2                             H      H      C.sub.6 H.sub.5                                                                      4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2             H      C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      3-F4-HOC.sub.6 H.sub.3 CH.sub.2                          2-CH.sub.3                                                                           2-CH.sub.3                                                                           4-CH.sub.3                                                                           3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4                               CH.sub.2                                                 4-CH.sub.3 O                                                                         4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub                         .3)                                                      4-CH.sub.3                                                                           2-Cl   4-CH.sub.3                                                                           3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3                               CH.sub.2                                                 4-CH.sub.3                                                                           4-Br   4-OCH.sub.3                                                                          3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                 4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH.sub.2                                                 4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH(C.sub.2 H.sub.5)                                      4-CH.sub.3                                                                           4-C.sub.6 H.sub.5                                                                    4-Cl   2-furylmethyl-                                           4-Cl   2-Cl   4-Cl   5-methyl-2-furylmethyl-                                  3-Cl   4-CH.sub.3                                                                           4-CH.sub.3                                                                           2-thienylmethyl-                                         4-CH.sub.3 O                                                                         4-CH.sub.3 O                                                                         4-CH.sub.3 O                                                                         5-methyl-2-thienylmethyl-                                4-F    4-Br   4-F    1-(2-furyl)ethyl-                                        2-Cl   2-F    4-Br   1-(5-methyl-2-furyl)ethyl-                               __________________________________________________________________________

EXAMPLE 187-(N-Triphenylmethylamino)-3-methyl-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]-.DELTA.³-cephem

7-(N-Triphenylmethylamino)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-.DELTA.³-cephem (2.8 g.) in ethanol-free chloroform (7.5 ml.) containingpyridine (0.6 g.) is treated with phosgene in chloroform (3.7 ml.,1.7M). The reaction is allowed to stir for 30 min. at room temperature.The excess phosgene is removed under reduced pressure and additionalchloroform added until the volume of solution is 10 ml.Tetramethylguanidine hydrogen azide (2.4 g.) in chloroform (5 ml.) isadded to the above prepared solution and the reaction allowed to stir atroom temperature for 20 min. The solution is washed with water, dried(MgSO₄) and evaporated under reduced pressure to give an oil.Trituration with light petroleum ether gives 2.2 g. of the desiredproduct.

NMR (CDCl₃): δ = 7.2, 19H; 5.3(s) 2H; 4.4(q) 1H; 4.2(d) 1H; 3.6(s) 3H;3.0, 3H and 1.2(s) 3H.

EXAMPLE 19

The following Δ³ -cephems are prepared by repeating the procedure ofExample 18, starting with the appropriate intermediates of Examples 16and 17:

    __________________________________________________________________________     ##STR33##                                                                    R.sub.3                                                                              R.sub.4                                                                              R.sub.5    R.sub.2                                              __________________________________________________________________________    H      H      H      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2     H      H      H      4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3                                C.sub.2                                                  H      H      H      2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 H      H      H      3-ClHOC.sub.6 H.sub.3 CH.sub.2                           H      H      H      3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2          H      H      H      4-HOC.sub.6 H.sub.4 CH(CH.sub.3 )                        H      H      H      2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 H      H      H      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                    H      H      H      2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)      H      H      H      4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)        H      H      H      3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2           H      H      H      4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2      H      H      H      3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2          H      H      H      4-HOC.sub.6 H.sub.4 CH(φ)                            H      H      H      3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                  H      H      H      4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH.sub.2                                                 H      H      H      3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6                                H.sub.3 CH.sub.2                                         H      H      H      4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                 H      H      H      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)          H      H      H      3-F4-CH.sub.3 OC.sub.6 H.sub.3 C.sub.2                   H      H      H      3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)             H      H      H      4-HOC.sub.6 H.sub.4 CH.sub.2                             H      H      H      4-CH.sub.3 C.sub.2 C.sub.6 H.sub.4 CH.sub.2              H      H      H      3-F4-HOC.sub.6 H.sub.3 CH.sub.2                          H      H      H      3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4                               CH.sub.2                                                 H      H      H      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub                         .3)                                                      H      H      H      3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3                               CH.sub.2                                                 H      H      H      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                 H      H      H      4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH.sub.2                                                 H      H      H      4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH(C.sub.2 H.sub.5)                                      H      H      H      2-furylmethyl-                                           H      H      H      5-methyl-2-furylmethyl-                                  H      H      H      2-thienylmethyl-                                         H      H      H      5-methyl-2-thienylmethyl-                                H      H      H      1-(2-furyl)ethyl-                                        H      H      H      1-(5-methyl-2-furyl)ethyl-                               H      H      4-CH.sub.3                                                                           4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2     H      H      2-CH.sub.3                                                                           4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3                                CH.sub.2                                                 H      H      3-CH.sub.3 O                                                                         2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 H      H      4-CH.sub.3 O                                                                         4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                         H      H      2-F    2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 H      H      4-F    2,4-(CH.sub.3 O0.sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)      H      H      3-Cl   4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2      H      H      4-Cl   3-CH4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 H      H      4-Br   3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2          H      4-CH.sub.3                                                                           4-CH.sub.3                                                                           3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                  H      4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH.sub.2                                                 H      4-CH.sub.3                                                                           4-CH.sub.3 O                                                                         3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6                                H.sub.3 CH.sub.2                                         H      4-CH.sub.3 O                                                                         4-CH.sub.3 O                                                                         4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                 H      3-CH.sub.3 O                                                                         3-F    4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)          H      3-CH.sub.3 O                                                                         4-F    3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2          H      3-CH.sub.3 O                                                                         4-F    3-F4-CH 3OC.sub.6 H.sub.3 CH.sub.2                       H      4-Cl   3-Cl   3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)             H      4-Cl   4-F    4-HOC.sub.6 H.sub.4 CH.sub.2                             H      4-Cl   4-Br   4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                         H      4-Br   4-Br   4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2             H      3-Br   4-CH.sub.3 O                                                                         3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                         H      4-Br   4-CH.sub.3                                                                           3-Cl4-CH.sub. 3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2        H      H      C.sub.6 H.sub.5                                                                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub                         .3)                                                      H      C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3                               CH.sub.2                                                 2-CH.sub.3                                                                           2-CH.sub.3                                                                           4-CH.sub.3                                                                           2-F4-HOC.sub.6 H.sub.3 CH.sub.2                          4-CH.sub.3 O                                                                         4-CH.sub.3                                                                           4-CH.sub.3                                                                           3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                 4-CH.sub.3                                                                           2-Cl   4-CH.sub.3                                                                           4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4                                 CH.sub.2                                                 4-CH.sub.3                                                                           4-Br   4-OCH.sub.3                                                                          2-furylmethyl-                                           4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-CH.sub.3                                                                           5-methyl-2-furylmethyl-                                  4-CH.sub.3                                                                           4-CH.sub.3                                                                           4-CH.sub.3                                                                           2-thienylmethyl-                                         4-CH.sub.3                                                                           4-C.sub.6 H.sub.5                                                                    4-Cl   1-(2-furyl)ethyl-                                        4-Cl   2-Cl   4-Cl   1-(5-methyl-2-furyl)ethyl-                               __________________________________________________________________________

EXAMPLE 20 7-Amino-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem

7-(N-Triphenylmethylamino)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-.DELTA.³-cephem (1.5 g.) is treated with formic acid (30 ml.) and the solutionallowed to stand at room temperature for 30 min. The solution is pouredinto water (100 ml.) and the aqueous suspension washed with ethylacetate. The aqueous solution is adjusted to pH 7.5 with 2N aqueoussodium hydroxide and the mixture extracted with chloroform. The organicsolution is dried (MgSO₄) and evaporated under reduced pressure to leavea foam. Trituration with light petroleum ether gives 400 mg. of thedesired product as a solid.

NMR (CDCl₃): δ = 7.0(q) 4H; 5.4(s) 2H; 4.9(d) 1H; 4.6(d) 1H; 3.7(s) 3H;3.3(q) 2H; 2.0(s) 2H and 1.4(s) 3H.

In a similar manner, when the compounds of Example 19 are subjected tothe above hydrolysis conditions, the following 7-amino-Δ³ -cephems areproduced, said products being identical with those of Example 6:

    ______________________________________                                         ##STR34##                                                                               R.sub.11                                                           ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.6 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 217-[D-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem

A.7-[d-(α-t-Butoxycarboxamido-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem

D-(α-t-Butoxycarboxamido-α-phenyl)acetic acid (0.251 g.) intetrahydrofuran (2 ml.) is treated with triethylamine (0.101 g.) andethyl chloroformate (0.108 g.) at -10° C. After 15 min. at thistemperature, the sodium salt of 7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem (0.400 g.) in water (3 ml.) is added with stirring in oneportion. The mixture is diluted with tetrahydrofuran (2 ml.) and allowedto warm up to room temperature. After one hr. the solution is adjustedto pH 2 with 2N hydrochloric acid and the suspension extracted withethyl acetate. The ethyl acetate solution is washed with water dried(MgSO₄), concentrated under reduced pressure, and poured into a largevolume of light petroleum ether to give a white solid. The compound isrecrystallized from chloroform (316 ml.).

NMR (DMSOd₆): δ = 7.6(d) 1H; 7.2, 5H; 6.0(d) 1H; 5.6(q) 1H; 5.2(d) 1H;4.9(d) 1H; 3.3(q) 2H; 2.0(s) 3H and 1.2(s) 9H.

b. 7-[d-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem trifluoroacetate

7-[D-(α-t-Butoxycarboxamido-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem (26 mg.) is dissolved in trifluoroacetic acid (0.5 ml.) andallowed to stand at room temperature for 20 min. To the solution isadded ether and the precipitate collected (24 mg.).

NMR (DMSOd₆ --D₂ O): δ = 7.4(s) 5H; 5.6(d) 1H; 5.1(d) 1H; 5.0(s) 1H;3.4, 2H and 2.0(s) 3H.

EXAMPLE 227-[D-α-Amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem

The procedures of Example 21A and B are repeated, starting with therequisite D-[α-t-butoxycarboxamido-α-(p-hydroxyphenyl)]acetic acid inplace of D-(α-t-butoxycarboxamido-α-phenyl)acetic acid, to provide thedesired product.

IR (CH₂ Cl₂): γ_(max) : 1780 cm.sup.⁻¹ (β-lactam carbonyl); 1660 cm⁻ ¹(--CONH--).

EXAMPLE 23

The procedures of Example 21A and B are again repeated, starting withthe appropriate α-amino acid derivative, said compounds being preparedby known procedures such as those taught by Greenstein and Winitz in"Chemistry of Amino Acids," John Wiley and Sons, Inc., New York/London,1961, p. 698-700 and the references cited therein; and resolved intotheir optical isomers by the methods taught by Greenstein and Winitz,loc. cit., p. 715-755, Nishimura et al., Nippon Kagaku Zasshi, 82, 1688(1961), Belg. Pat. 795,874 and British Pat. No. 1,221,227, to providethe following cephem analogs:

    ______________________________________                                         ##STR35##                                                                    Ar               *(configuration)                                             ______________________________________                                        3-HOC.sub.6 H.sub.4                                                                            D                                                            3,4-(HO).sub.2 C.sub.6 H.sub.3                                                                  DL                                                          4-(CH.sub.3 O)C.sub.6 H.sub.4                                                                  D                                                            4-HOC.sub.6 H.sub.4                                                                            L                                                            2-thienyl-       D                                                            3-Cl4-HOC.sub.6 H.sub.3                                                                        D                                                            4-ClC.sub.6 H.sub.4                                                                             DL                                                          3-ClC.sub.6 H.sub.4                                                                             DL                                                          4-FC.sub.6 H.sub.4                                                                             D                                                            2-Br5-HOC.sub.6 H.sub.3                                                                         DL                                                          3-FC.sub.6 H.sub.4                                                                             D                                                            4-FC.sub.6 H.sub.4                                                                             L                                                            2-ClC.sub.6 H.sub.4                                                                            D                                                            2-ClC.sub.6 H.sub.4                                                                            L                                                            3-BrC.sub.6 H.sub.4                                                                            D                                                            3-BrC.sub.6 H.sub.4                                                                            L                                                            3-ClC.sub.6 H.sub.4                                                                            D                                                            4-ClC.sub.6 H.sub.4                                                                            D                                                            2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                    DL                                                          3,4-Cl.sub.2 C.sub.6 H.sub.3                                                                    DL                                                          2-FC.sub.6 H.sub.4                                                                             D                                                            3-FC.sub.6 H.sub. 4                                                                            D                                                            3-FC.sub.6 H.sub.4                                                                             L                                                            4-BrC.sub.6 H.sub.4                                                                            D                                                            3-HOC.sub.6 H.sub.4                                                                            L                                                            4-HOC.sub.6 H.sub.4                                                                             DL                                                          3-CH.sub.3 C.sub.6 H.sub.4                                                                     D                                                            3-CH.sub.3 C.sub.6 H.sub.4                                                                     L                                                            2-CH.sub.3 OC.sub.6 H.sub.4                                                                     DL                                                          3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                          DL                                                          3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                         D                                                            3-thienyl-       D                                                            3-thienyl-        DL                                                          4-H.sub.2 NC.sub.6 H.sub.4                                                                     D                                                            3-H.sub.2 NC.sub.6 H.sub.4                                                                     D                                                            3-Cl4-H.sub.2 NC.sub.6 H.sub.3                                                                 D                                                            3-Cl5-(CH.sub.3 O)C.sub.6 H.sub.3                                                              D                                                            2-Cl4-CH.sub.3 C.sub.6 H.sub.3                                                                  DL                                                          2-F3-CH.sub.3 C.sub.6 H.sub.3                                                                  D                                                            2-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                           DL                                                          ______________________________________                                    

EXAMPLE 247-(D-α-Hydroxyphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ.sup.3-cephem

A. 7-(d-α-formyloxyphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ.sup.3-cephem

D-O-Formylmandelic acid (1.8 g.) in ether (15 ml.) is treated withoxalyl chloride (2.5 ml.) and one drop of dimethylformamide. After thevigorous reaction has subsided (30 min.) the ether is removed underreduced pressure and the residue in THF (10 ml.) is added to a stirredsolution of 7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem (1 g.) inwater/THF mixture (1:1; 20 ml.) containing excess sodium bicarbonate.After stirring for a further hour at room temperature the mixture isadjusted to pH 2 with 2N hydrochloric acid and the mixture extractedwith ethyl acetate. The organic solution is washed with water, dried(MgSO₄), and evaporated under reduced pressure to leave the requiredproduct as a solid (350 mg.).

NMR (DMSOd₆): δ = 8.2(s) 1H; 7.2(s) 5H; 6.0(s) 1H; 5.5(q) 1H; 5.1(d) 1H;3.5(s) 2H and 2.0, 3H.

b. 7-(d-α-hydroxyphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ.sup.3-cephem

7-(D-α-Formyloxyphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ.sup.3-cephem (0.34 g.) is dissolved in excess aqueous sodium bicarbonate andallowed to stand at 30° C. for 3 hrs. The solution is adjusted to pH 2with 2N hydrochloric acid and the suspension extracted with ethylacetate. The organic solution is dried (MgSO₄) and evaporated underreduced pressure to leave the required product as a solid (0.26 g.).

NMR (DMSOd₆): δ = 9.0, 1H; 7.3(s) 5H; 5.6(q) 1H; 5.2(d) 1H; 5.1(s) 1H;3.6(s) 2H and 2.0(s) 3H.

EXAMPLE 25

Starting with the requisite mandelic acid derivative, prepared by themethod as taught in "Organic Synthesis," John Wiley and Sons, Inc., NewYork/London, 1956, Coll. Vol. I, p. 336, and employing the procedure ofExample 24, the following congeners are synthesized:

    ______________________________________                                         ##STR36##                                                                    Ar               *(configuration)                                             ______________________________________                                        2-ClC.sub.6 H.sub.4                                                                            D                                                            3-ClC.sub.6 H.sub.4                                                                            D                                                            4-ClC.sub.6 H.sub.4                                                                             DL                                                          2-FC.sub.6 H.sub.4                                                                             L                                                            4-FC.sub.6 H.sub.4                                                                             D                                                            4-FC.sub.6 H.sub.4                                                                             L                                                            3-BrC.sub.6 H.sub.4                                                                             DL                                                          3-CH.sub.3 C.sub.6 H.sub.4                                                                     D                                                            4-CH.sub.3 C.sub.6 H.sub.4                                                                      DL                                                          4-CH.sub.3 OC.sub.6 H.sub.4                                                                    D                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                                     DL                                                          3-CH.sub.3 OC.sub.6 H.sub.4                                                                    D                                                            2-HOC.sub.6 H.sub.4                                                                            D                                                            3-HOC.sub.6 H.sub.4                                                                            D                                                            4-HOC.sub.6 H.sub.4                                                                             DL                                                          4-HOC.sub.6 H.sub.4                                                                            D                                                            3-H.sub.2 NC.sub.6 H.sub.4                                                                     D                                                            2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                   D                                                            2,3-Cl.sub.2 C.sub.6 H.sub.3                                                                    DL                                                          3,5-Cl.sub.2 C.sub.6 H.sub.3                                                                   D                                                            2-Cl4-FC.sub.6 H.sub.3                                                                         D                                                            3-Cl4-FC.sub.6 H.sub.3                                                                          DL                                                          3-Cl4-BrC.sub.6 H.sub.3                                                                        L                                                            3,4-Br.sub.2 C.sub.6 H.sub.3                                                                   D                                                            3-F4-CH.sub.3 C.sub.6 H.sub.3                                                                   DL                                                          3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                          D                                                            3,4-(HO).sub.2 C.sub.6 H.sub.3                                                                 D                                                            3-Cl4-HOC.sub.6 H.sub.3                                                                        L                                                            2-F4-HOC.sub.6 H.sub.3                                                                          DL                                                          2-F4-CH.sub.3 OC.sub.6 H.sub.3                                                                  DL                                                          3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                         D                                                            3-CH.sub.3 O4-HOC.sub.6 H.sub.3                                                                D                                                            3-Br5-HOC.sub.6 H.sub.3                                                                        L                                                            3-H.sub.2 N4-HOC.sub.6 H.sub.3                                                                 D                                                            3-H.sub.2 N4-CH.sub.3 OC.sub.6 H.sub.3                                                          DL                                                          3-CH.sub.34-H.sub.2 NC.sub.6 H.sub.3                                                           D                                                            ______________________________________                                    

EXAMPLE 26 7-(2-Cyanoacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem

To a stirred suspension of 7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephemtosylate salt (576 mg.) in methylene chloride (20 ml.) under nitrogen,is added triethylamine (450 mg.). After stirring for 20 min. at roomtemperature, this solution is then treated with the N-hydroxysuccinimideester of cyanoacetic acid (470 mg.) all in one portion. After stirringovernight, under nitrogen, the reaction mixture is poured into water (30ml.) and the pH of the aqueous phase is adjusted to 8.0. The methylenechloride layer is separated off. The aqueous phase is acidified to pH 2,and then extracted with ethyl acetate. The ethyl acetate is washed withwater, dried (sodium sulfate) and the solvent removed under vacuum.Trituration of the residue with dry ether gives the product as a paleyellow solid (55 mg.).

NMR (DMSOd₆): δ = 5.7(q) 1H; 5.2(d) 1H; 3.8(s) 2H; 3.6(s) 2H and 2.0 (d)6H.

EXAMPLE 27 7-(2-Carboxyphenylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem sodium salt

Phenyl malonic acid (0.79 g.) is dissolved in distilled water (25 ml.)and the pH of the solution adjusted to 6.0 by adding 2N sodium hydroxidesolution. A solution of 7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem(0.65 g.) in 10 ml. distilled water (pH adjusted to 6 by addition of 2Nsodium hydroxide solution) is then added, and the reaction mixturecooled to 0° C. 1-Ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide (1.6g.) is added and the solution stirred to 3.5 hrs., during which time thepH is maintained in the range 6.1 to 6.3 by the dropwise addition ofdilute hydrochloric acid. At this point, the pH is raised to 7.3 by theaddition of saturated sodium bicarbonate solution, and the reactionmixture is extracted with ethyl acetate. The extract is discarded. Theaqueous phase is then acidified to ph 3 using 0.4M phosphoric acid, andagain extracted with ethyl acetate (two 50 ml. portions). The latterextract is dried, and concentrated to a volume of about 25 ml. To thissolution is then added a solution of sodium 2-ethylhexanoate (1 g.) in20 ml. of ethyl acetate. The precipitate which forms is filtered to give0.75 g. of the disodium salt of7-(2-carboxy-2-phenylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem.The infrared spectrum of the product (KBr disc) shows absorptions at1760 cm⁻ ¹ (β-lactam carbonyl), 1660 cm⁻ ¹ (amide I band) and 1600 cm⁻ ¹(carboxylate carbonyl).

NMR (D₂ O): δ = 7.4(m) 5H; 5.7(d) 1H; 5.2(d) 1H; 3.4(m) 2H and 1.9 (s)3H.

EXAMPLE 28

Substituting 2-thienyl malonic acid for phenyl malonic acid in theprocedure of Example 27, leads to the synthesis of7-[α-(2-thienyl)-α-carboxyacetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem.

NMR (DMSOd₆): δ = 2.1(s) 3H; 3.3(m) 2H; 5(s) 1H; 5.6(m) 1H; 6.8-7.5 (m)3H.

IR (KBr disc) γ_(max) 1770 cm⁻ ¹ (β-lactam carbonyl); 1670 cm⁻ ¹(--CONH--).

Similarly, by employing the appropriate malonic acid derivative andrepeating the procedure of Example 27, the following compounds areprepared:

    ______________________________________                                         ##STR37##                                                                               Ar                                                                 ______________________________________                                               2-ClC.sub.6 H.sub.4                                                           4-ClC.sub.6 H.sub.4                                                           3-BrC.sub.6 H.sub.4                                                           2-FC.sub.6 H.sub.4                                                            4-FC.sub.6 H.sub.4                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                   2-CH.sub.3 C.sub.6 H.sub.4                                                    4-CH.sub.3 C.sub.6 H.sub.4                                                    4-HOC.sub.6 H.sub.4                                                           4-H.sub.2 NC.sub.6 H.sub.4                                                    2,4-Cl.sub.2 C.sub.6 H.sub.3                                                  3,4-F.sub.2 C.sub.6 H.sub.3                                                   3-F4-BrC.sub.6 H.sub.3                                                        3-Cl4-HOC.sub.6 H.sub.3                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                        3-F4-CH.sub.3 OC.sub.6 H.sub.3                                                3-Cl 4-H.sub.2 NC.sub.6 H.sub.3                                               3-thienyl-                                                             ______________________________________                                    

EXAMPLE 29 7-Phenylacetamido-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem

Phenacetyl chloride (2.3 g.) in acetone (5 ml.) is added dropwise to astirred solution of 7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem sodiumsalt (1.31 g.) in aqueous acetone (20 ml.) over 20 min. at roomtemperature. Sodium hydroxide (2N) is added simultaneously to keep pH at8±0.5. The solution, after the addition, is stirred for a further 15min. The acetone is removed under reduced pressure and the pH of theaqueous solution adjusted to 2 with 2N hydrochloric acid. The suspensionis extracted with ethyl acetate, the organic solution dried (MgSO₄) andevaporated under reduced pressure to leave an oil which solidifies aftertrituration with ether (440 mg.).

NMR (DMSOd₆): δ = 9.0(d) 1H; 7.2(s) 5H; 5.6(q) 1H; 5.2(d) 1H; 3.5(s) 4Hand 2.0(s) 3H.

EXAMPLE 30 7-Phenoxyacetamido-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem

Phenoxyacetyl chloride (2.56 g.) in acetone (5 ml.) is added dropwise toa stirred solution of 7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephemsodium salt (1.31 g.) in aqueous acetone (30 ml.) over 20 min. at roomtemprature. Sodium hydroxide (2N) is added simultaneously to keep the pHat 8±0.5. The solution is then allowed to stir for a further 15 min. Theacetone is removed under reduced pressure and the pH of the aqueoussolution adjusted to 2 with hydrochloride acid (2N). The suspension isextracted with ethyl acetate and the organic solution dried (MgSO₄).Evaporation and trituration of the residue gives the desired product asa solid (370 mg.).

NMR (DMSOd₆): δ = 9.0(d) 1H; 7.0(m) 5H; 5.6(q) 1H; 5.2(d) 1H; 4.6(s) 2H;3.8(s) and 2.0(s) 2H.

EXAMPLE 31

Employing the procedure of Example 29 and 30, and starting with therequisite reagents, the following Δ³ -cephems are synthesized:

7-Bromoacetamido-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,

Nmr (dmsod₆): δ = 2.15(s) 3H; 3.7(m) 2H; 4.1(s) 2H; 5.4(d) 1H and 5.2(m) 1H;

7-(α-azido-α-phenylacetamido)-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem,

Nmr (dmsod₆): δ = 9.2(s) 1H; 7.35(s) 5H; 5.6(s) 1H; 5.15(q) 2H; 3.58 (s)2H and 1.98(s) 3H;

7-[α-(tetrazol-5-yl)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ.sup.3-cephem,

Nmr (dmsod₆): δ = 2.0(s) 3H; 3.6(s) 2H; 5.05-5.15(d) 1H; 5.15(s) 2H;5.5-5.8(q) 1H and 9.5(s) 1H;

7-(α-phenylthioacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,

Nmr (dmsod₆): δ = 9.18(d) 1H; 7.23(m) 5H; 5.63(q) 1H; 5.35(d) 1H;3.77(s) 2H; 3.6(m) 2H and 2.03(s) 3H;

7-[α-(2,6-dimethoxyphenyl)carboxamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem,

Nmr (dmsod₆): δ = 2.0(s) 3H; 3.6(s) 2H; 3.7(s) 6H; 5.05-5.15(d) 1H;5.5-5.8(q) 1H; 6.5-6.7(d) 2H and 7.0-7.3(m) 1H;

7-(2-thienylglyoxylamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,

Nmr (dmsod₆): δ = 2.0(s) 3H; 3.6(s) 2H; 5.1-5.15(d) 1H; 5.4-5.7(q) 1H;7.05-7.15(m) 1H and 7.8-8.1(m) 2H; and

7-[α-(2-thienyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem,

Nmr (dmsod₆): δ = 2.0(s) 3H; 3.6(s) 2H; 3.8(s) 2H; 5.1-5.15(d) 1H;5.5-5.8(q) 1H; 6.95-7.0(d) 2H and 7.1-7.2(m) 1H.

EXAMPLE 32

Starting with the appropriate acid chloride and7-amino-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem and employing theprocedure of Examples 29 and 30, the following cogeners are prepared:

    ______________________________________                                         ##STR38##                                                                           Ar            Q         n                                              ______________________________________                                        C.sub.6 H.sub.5      --        0                                              2-ClC.sub.6 H.sub.4  --        0                                              4-ClC.sub.6 H.sub.4  --        0                                              2,3-Cl.sub.2 C.sub.6 H.sub.3                                                                       --        0                                              3,4-Cl.sub.2 C.sub.6 H.sub.3                                                                       --        0                                              3-FC.sub.6 H.sub.4   --        0                                              4-FC.sub.6 H.sub.4   --        0                                              3,5-F.sub.2 C.sub. 6 H.sub.3                                                                       --        0                                              4-BrC.sub.6 H.sub.4  --        0                                              3,4-Br.sub.2 C.sub.6 H.sub.3                                                                       --        0                                              3-HOC.sub.6 H.sub.4  --        0                                              4-HOC.sub.6 H.sub.4  --        0                                              4-H.sub.2 NC.sub.6 H.sub.4                                                                         --        0                                              3-Cl4-HOC.sub.6 H.sub.3                                                                            --        0                                              3-F4-HOC.sub.6 H.sub.3                                                                             --        0                                              4-CH.sub. 3 OC.sub.6 H.sub.4                                                                       --        0                                              3-Br4-CH.sub.3 OC.sub.6 H.sub.3                                                                    --        0                                              3-CH.sub.34-HOC.sub.6 H.sub.3                                                                      --        0                                              3-CH.sub.34-ClC.sub.6 H.sub.3                                                                      --        0                                              2-thienyl-           --        0                                              3-thienyl-           --        0                                              2-ClC.sub.6 H.sub.4  N.sub.3   1                                              4-ClC.sub.6 H.sub.4  N.sub.3   1                                              2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                       N.sub.3   1                                              4-FC.sub.6 H.sub.4   N.sub.3   1                                              3,5-F.sub.2 C.sub.6 H.sub.3                                                                        N.sub.3   1                                              4-BrC.sub.6 H.sub.4  N.sub.3   1                                              4-HOC.sub.6 H.sub.4  N.sub.3   1                                              3-HOC.sub.6 H.sub.4  N.sub.3   1                                              4-CH.sub.3 OC.sub.6 H.sub.4                                                                        N.sub.3   1                                              3-F4-HOC.sub.6 H.sub.3                                                                             N.sub.3   1                                              3-Cl4-HOC.sub.6 H.sub.3                                                                            N.sub.3   1                                              3-Br4-CH.sub.3 OC.sub.6 H.sub.3                                                                    N.sub.3   1                                              4-H.sub.2 NC.sub.6 H.sub.4                                                                         N.sub.3   1                                              3-Cl4-H.sub.2 NC.sub.6 H.sub.3                                                                     N.sub.3   1                                              4-CH.sub.3 C.sub.6 H.sub.4                                                                         N.sub.3   1                                              3-CH4-CH.sub.3 OC.sub.6 H.sub.3                                                                    N.sub.3   1                                              2-thienyl-           N.sub.3   1                                              3-thienyl-           N.sub.3   1                                              ______________________________________                                    

EXAMPLE 337-[α-Hydroxy-α-(2-thienyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem

7-(2-Thienylglyoxylamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem (1.50g.) in water (30 ml.) is converted to the sodium salt with 2N sodiumhydroxide. This solution is cooled in ice and anhydrous sodium acetate(1.53 g.) is added. Sodium borohydride (276 mg.) is then added in smallportions over a 45 min. period. The pH is kept at 8, by adding glacialacetic acid alternately with sodium borohydride. After the additions,the pH is kept at 8 for 45 min. with the ice bath removed. The solutionis layered with ethyl acetate and the pH adjusted to 2 with 40%phosphoric acid. The organic layer is separated, washed with water,dried (Na₂ SO₄), filtered and concentrated in vacuo until solidscrystallize. The product is filtered, washed with dry ether and driedunder vacuum, 360 mg.

NMR (DMSOd₆): δ = 7.2(m) 1H; 7.0, 2H; 5.4(m) 1H; 5.0(s) 2H; 3.5, 2H and2.0(s) 3H.

EXAMPLE 347-[2-(2-methyl-1,3,4-thiadiazol-5-yl-thio-acetamido)]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem

Triethylamine (0.2 ml.) is added to a cold 0° C. suspension of7-(2-bromoacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem (0.5 g.) inmethylene chloride (15 ml.). To the resultant pale yellow solution isadded a slurry of 2-methyl-1,3,4-thiadiazole-5-thiol (0.19 g.) and thesolution stirred at 0° C. After 2 hrs. the product which hasprecipitated is collected by filtration (0.3 g.).

NMR (DMSOd₆): δ = 9.3(d) 1H; 5.6(m) 1H; 5.2(d) 1H; 4.15(s) 2H; 3.6 (s)2H; 2.7(s) 3H and 2.05(s) 3H.

EXAMPLE 35

The procedure of Example 34 is repeated, starting with7-(2-bromoacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem and1-methyl-5-mercaptotetrazole (Lieber, et al., Can. J. Chem., 37, 101[1959]) to provide

7-[α-(1-methyltetrazol-5-ylthio)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem.

NMR (DMSOd₆): δ = 9.28(d) 1H; 5.6(q) 1H; 5.24(d) 1H; 4.13(s) 2H; 3.95(s)3H; 3.59(m) 2H and 2.01(s) 3H.

EXAMPLE 36

Again, the procedure of Example 34 is repeated, employing4-mercaptopyridine and7-(2-bromoacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³ -cephem to give7-[2-(4-pyridylthio)acetamido]-3-methyl-4-tetrazol-5-yl)-Δ³ -cephem.

NMR (DMSOd₆): δ = 9.32(d) 1H; 8.41(m) 2H; 7.33(m) 2H; 5.7-5.6(q) 1H;5.25(d) 1H; 3.95(d) 2H; 3.6(m) 2H and 2.03(s) 3H.

EXAMPLE 707-(2',2',2'-Trichloroethoxycarboxamido)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem

A. 7-(2',2',2'-trichloroethoxycarboxamido)-3-acetoxymethyl-Δ³-cephem-4-carboxylic acid

Sodium bicarbonate (300 g.) is added portionwise to a stirred slurry of7-amino-cephalosporanic acid (408 g.) in aqueous acetone (2:1, 5 liters:2.5 liters). 2',2',2'-Trichloroethyl chloroformate (350 g.) is thenadded dropwise over 45 min. and the mixture stirred for a further 5 hrs.at room temperature.

The acetone is removed in vacuo, and the aqueous solution is thendiluted to 10 liters with distilled water. The pH of the solution isadjusted to 2 with 50% hydrochloric acid, and the mixture extracted withethyl acetate (5 × 1.5 liters). The combined organic layers are washedwith water (2 × 2 liters), dried (MgSO₄) and the solution concentratedto a volume of 1.5 liters.

The concentrate is slowly added to petroleum ether (b.p. 60°-80° C., 15liters) and the precipitated solid washed with petroleum ether (b.p.30°-40° C. 2 × 2 liters). The precipitate is dried in vacuo at 45° C. tofurnish 7-(2',2',2'-trichloroethoxycarbonyl)-amino-3-acetoxymethyl-Δ³-cephem-4-carboxylic acid as a white solid (490 g.).

NMR (DMSOd₆): δ = 10(d) 1H; 5.5(q) 1H; 5.1(d) 1H; 4.8(q) 2H; 4.8(s) 2H;3.5(s) 2H and 2.0(s) 3H.

b. 7-(2' ,2',2'-trichloroethoxycarboxamido)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)-carbamoyl]-Δ³-cephem

Starting with the acid of Example 37A and following the procedure ofExample 1B, the desired product is prepared in moderate yield.

NMR (CDCl₃): δ = 2.0(s) 3H; 3.4(s) 2H; 3.8(s) 3H; 4.45(d) 2H; 4.75 (s)2H; 4.9(m) 3H; 5.5(q) 1H; 6.2(b) 1H and 7.1(q) 4H.

EXAMPLE 387-(2',2',2'-Trichloroethoxycarboxamido)-3-(2-methyl-1,3,4thiadiazol-5-ylthiomethyl)-4-[N-(p-methoxybenzyl)-carbamoyl]-Δ³-cephem

A.7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-Δ³-cephem-4-carboxylic acid

Following the procedure of Example 37A, but employing as the cephem7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-Δ³-cephem-4-carboxylic acid (U.S. Pat. No. 3,641,021), the desired productis prepared.

NMR (CDCl₃): δ = 5.4(m) 2H; 5.1(d) 1H; 4.85(s) 2H; 4.4(q) 2H; 3.7(s) 2Hand 2.7(s) 3H.

b.7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem

Employing the product of Example 38A and using the procedure of Example37B and 1B, the desired intermediate product is synthesized.

NMR (CDCl₃): δ = 7.0(q) 2H; 6.1(m) 1H; 5.4(q) 1H; 4.9(d) 1H; 4.7(s) 2H;4.4(m) 4H; 3.75(s) 3H and 3.6(s) 2H.

EXAMPLE 39

The procedure of Example 37 is repeated, starting with the appropriate2',2',2'-trihaloethyl chloroformate, Δ³ -cephem-4-carboxylic acid andamine, to give the following analogs:

    ______________________________________                                         ##STR39##                                                                    R                    R.sub.2                                                  ______________________________________                                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Cl.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Cl.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                          Cl.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)              Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.6 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(φ)                                  Cl.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Cl.sub.3 CCH.sub.2 OCO                                                                       3-CL4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2                      H.sub.5)                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Cl.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-thienylmethyl-                                      Cl.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Cl.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       2-ClCH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                         Br.sub.3 CCH.sub.2 OCO                                                                       4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Br.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub. 2)C.sub.6 H.sub.4 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2               Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub. 2 OC.sub.6 H.sub.3 CH(CH.sub.3)      Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Br.sub.3 CCH.sub.2 OCO                                                                       2-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Br.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Br.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Br.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Br.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     ______________________________________                                    

EXAMPLE 40

The procedure of Example 38 is repeated, starting with the requisitereagents, to give the following analogs:

    ______________________________________                                         ##STR40##                                                                    R                     R.sub.2                                                 ______________________________________                                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Cl.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Cl.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub. 4 CH(φ)                         Cl.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)              Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.6 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(φ)                                  Cl.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Cl.sub.3 CCH.sub. 2 OCO                                                                      3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2                      H.sub.5)                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Cl.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-thienylmethyl-                                      Cl.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Cl.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub. 2 C.sub.6 H.sub.4 CH.sub.2           Br.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2               Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Br.sub.3 CCH.sub.2 OCO                                                                       2-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Br.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Br.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Br.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Br.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     ______________________________________                                    

EXAMPLE 417-(2',2',2'-Trichloroethoxycarboxyamido)-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem

Phosphorous pentachloride (1.68 g., 8 mmole) is added to a stirredsolution of7-(2',2',2'-trichloroethoxycarboxamido)-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem (2.26 g., 4 mmole) and pyridine (0.64 g., 8 mmole) in dry,ethanol-free chloroform (30 ml.) at 0°-5° C. After 30 min., NMRindicated that the amide had completely reacted (disappearance of the 2proton double at δ4.45). A solution of tetramethylguanidinium azide (6.3g., 40 mmole) in dry ethanol-free chloroform (20 ml.) is added dropwiseover a period of 10 min. to the cooled solution. After a further 10 min.the ice-bath is removed and the reaction mixture is stirred at ambienttemperature for 30 min. The reaction mixture is washed with water,aqueous sodium bicarbonate solution (3 x), 6N hydrochloric acid (3 x),water, and dried over magnesium sulphate. Evaporation of the solventaffords the crude product as a pale brown solid (1.5 g.). Columnchromatography on silica gel commencing with hexane as eluent and addinggradually increasing proportions of ether, finally eluting with 100%ether affords the pure (by tlc) product.

NMR (DMSOd₆): δ = 1.8(s) 3H; 3.6(q) 2H; 3.9(s) 3H; 4.2(q) 2H; 4.8(s) 2H;5.1(d) 1H; 5.6(m) 3H; 6.3(d) 1H and 7.4(q) 4H.

EXAMPLE 427-(2',2',2'-Trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem

Starting with the cephem of Example 38B and following the procedure ofExample 41, the desired product is synthesized.

NMR (CDCl₃): δ = 7.0(q) 4H; 5.5(s) 2H; 5.4(m) 2H; 4.7(s) 2H; 4.1(m) 2H;5.75(s) 3H and 5.65(m) 2H.

EXAMPLE 43

Starting with the intermediates of Example 39, and employing theprocedure of Example 41, the following Δ³ -cephems are synthesized:

    ______________________________________                                         ##STR41##                                                                    R                     R.sub.11                                                ______________________________________                                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Cl.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Cl.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                          Cl.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub. 6 H.sub.3 CH(CH.sub.3)           Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)              Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.6 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(φ)                                  Cl.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2                      H.sub.5)                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Cl.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-thienylmethyl-                                      Cl.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Cl.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Br.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2               Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Br.sub.3 CCH.sub.2 OCO                                                                       2-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Br.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Br.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Br.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Br.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     ______________________________________                                    

EXAMPLE 44

In a manner similar to the procedure of Example 41, and starting withthe intermediates of Example 40, the following congeners aresynthesized:

    ______________________________________                                         ##STR42##                                                                    R                     R.sub.11                                                ______________________________________                                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Cl.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Cl.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ )                         Cl.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)              Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.6 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(φ)                                  Cl.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Cl.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Cl.sub.3 CCH.sub.2 OCO                                                                       3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Cl.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Cl.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Cl.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Cl.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2                      H.sub.5)                                                       Cl.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Cl.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Cl.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-thienylmethyl-                                      Cl.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Cl.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2           Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2        Br.sub.3 CCH.sub.2 OCO                                                                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)            Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2            Br.sub.3 CCH.sub.2 OCO                                                                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                 Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-I4-CH.sub. 3 OC.sub.6 H.sub.3 CH.sub.2                       Br.sub.3 CCH.sub.2 OCO                                                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3                        CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                       Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                Br.sub.3 CCH.sub.2 OCO                                                                       3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                        Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH.sub.2                                   Br.sub.3 CCH.sub.2 OCO                                                                       4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                               Br.sub.3 CCH.sub.2 OCO                                                                       4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                   Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-CH.sub.3 CO.sub. 2 C.sub.6 H.sub.3 CH.sub.2              Br.sub.3 CCH.sub.2 OCO                                                                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)       Br.sub.3 CCH.sub.2 OCO                                                                       3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2       Br.sub.3 CCH.sub.2 OCO                                                                       2-F4-HOC.sub.6 H.sub.3 CH.sub.2                                Br.sub.3 CCH.sub.2 OCO                                                                       3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3                          CH.sub.2                                                       Br.sub.3 CCH.sub.2 OCO                                                                       4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2         Br.sub.3 CCH.sub.2 OCO                                                                       2-furylmethyl-                                                 Br.sub.3 CCH.sub.2 OCO                                                                       5-methyl-2-furylmethyl-                                        Br.sub.3 CCH.sub.2 OCO                                                                       2-thienylmethyl-                                               Br.sub.3 CCH.sub.2 OCO                                                                       1-(2-furyl)ethyl-                                              Br.sub.3 CCH.sub.2 OCO                                                                       1-(5-methyl-2-furyl)ethyl-                                     ______________________________________                                    

EXAMPLE 457-Amino-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³ -cephem

Activated zinc dust (300 mg.) is added to a stirred solution of7-(2',2',2'-trichloroethoxycarboxamido-3-acetoxymethyl-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]-Δ³-cephem (300 mg. 0.5 mmole) in 90% acetic acid (3 ml.) and thesuspension is stirred at ambient temperature for 30 min. The reactionmixture is filtered, and evaporated to dryness. The resultant yellowfoam is dissolved in chloroform, and the solution extracted twice withdilute hydrochloric acid. The aqueous extracts are mixed withchloroform, and dilute sodium hydroxide is added to the stirred mixtureto pH 7.0. The mixture is filtered to remove precipitated inorganicsalts, the layers separated, and the aqueous solution extracted twicewith chloroform. The combined organic extracts are washed with water anddried over magnesium sulphate. Evaporation of the solvent affords theproduct as a pale yellow solid (110 mg.), pure by t.l.c.

NMR (CDCl₃): δ = 1.9(s) 1H; 2.0(s) 3H; 3.45(q) 2H; 3.8(s) 3H; 4.3(q) 2H;3.8(s) 3H; 4.3(q) 2H; 4.65(d) 1H; 4.95(d) 1H; 5.5(s) 2H and 7.1(q) 4H.

Similarly, starting with7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem and following the procedure of Example 45,7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem is prepared.

NMR (CDCl₃): δ = 7.0(q) 4H; 5.55(s) 2H; 4.9(d) 1H; 4.6(m) 1H; 3.8 (s)3H; 3.65(m) 2H and 2.7(s) 3H.

EXAMPLE 46

The procedure of Example 45 is repeated, starting with the intermediateΔ³ -cephems of Examples 43 and 44, to give the following analogs:

    ______________________________________                                         ##STR43##                                                                           R.sub.11                                                               ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.4 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                        and                                                                            ##STR44##                                                                           R.sub.11                                                               ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.4 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 477-Amino-3-(2-methyl-1,3,4-triadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-.DELTA.³-cephem

7-Amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem (125 mg.) is dissolved in acetone (2 ml.) and p-toluenesulphonicacid (60 mg.) in acetone (1 ml.) added. The salt precipitates out as abrown oil after addition of ether to this mixture. The solvent isdecanted and the residue washed (3 x) with ether (30 ml.). The residualoil is dissolved in trifluoroacetic acid/Anisole (4:1 v/v; 2 ml.) andheated on a water bath, in a stoppered flask (25 ml.) for 3 hrs. at 38°C.

At the end of this time the reaction is poured into dry ether, theorganic solvents decanted from the instantly formed precipitate, and theresidual solids washed with further portions of ether (3 × 30 ml.). Thecrude deprotected material was taken up in acetone/water (pH 2.5),extracted with ethyl acetate, the pH of the aqueous phase adjusted to7.6 with aqueous sodium hydroxide (2N) and re-extracted with ethylacetate. Concentration of the aqueous phase in vacuo, to dryness,affords a solid. This compound is characterized by acylation of theabove sodium salt with 2',2',2'-trichloroethoxycarbonyl chloride usingthe procedure of Example 1A to give7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-triadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ³-cephem.

NMR (CDCl₃): δ = 4.7(d) 1H; 4.2(m) 1H; 5.1(s) 2H; 5.35(s) 2H; 6.0(m) 2Hand 7.2(s) 3H.

EXAMPLE 48

Similar to the procedure of Example 47, and starting with the compoundsof Example 46, 7-amino-3-acetoxymethyl-4-(tetrazol-5-yl)-Δ³ -cephem and7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-.DELTA.³-cephem are prepared.

EXAMPLE 49

Sodium bicarbonate (42 g., 0.5 mole) is added gradually to a vigorouslystirred suspension of 7-amino-3-acetoxymethyl-Δ³ -cephem-4-carboxylicacid (50 g., 0.18 mole) in acetone/water (250/500 ml.). A solution ofbenzyl chloroformate (36 g., 0.21 mole) in acetone (70 ml.) is addeddropwise to the stirred solution over a period of 45 min. After stirringfor six hrs. the acetone is removed on the rotary evaporator and theaqueous residue washed with ethyl acetate to remove impurities. Theaqueous solution is overlaid with ethyl acetate and acidified to pH 4.0.The combined ethyl acetate solutions from the extractions of the aqueoussolution are washed with water and dried over magnesium sulphate.Evaporation of the ethyl acetate affords the product,7-benzyloxycarboxamido-3-acetoxymethyl-Δ³ -cephem-4-carboxylic acid, asan off-white solid (56 g.), pure by t.l.c.

NMR (DMSOd₆): δ = 2.0(s) 3H; 3.5(s) 2H; 4.8-5.2(m) 5H and 7.3(s) 5H.

Similarly are prepared7-benzyloxycarboxamido-3-(1-methyltetrazol-5-ylthiomethyl)-Δ³-cephem-4-carboxylic acid,

NMR (DMSOd₆): δ = 7.5(s) 5H; 6.6(d) 1H; 6.2(s) 3H; 4.4(b) 2H; 4.04(s) 3Hand 3.8(s) 2H;

7-benzyloxycarboxamido-3-methyl-Δ³ -cephem-4-carboxylic acid; and

7-benzyloxycarboxamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-Δ³-cephem-4-carboxylic acid.

EXAMPLE 507-Benzyloxycarboxamido-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-.DELTA.³-cephem

A solution of 2,4-dinitrophenol (22 g., 0.1 mole) in methylene chloride(100 ml.) is added to a solution of7-benzyloxycarboxamido-3-acetoxymethyl-Δ³ -cephem-4-carboxylic acid (41g., 0.1 mole) in dry dioxane (400 ml.). To this stirred solution isadded a solution of dicyclohexylcarbodiimide (21 g., 0.1 mole) indioxane (100 ml.). After 1.5 hr. the precipitate of dicyclohexylurea isremoved by filtration. To the filtrate is added a solution ofp-methoxybenzylamine (13.7 g., 0.1 mole) in dioxane (100 ml.). Afterstirring for 6 hrs. the precipitated solid is filtered, washed withether and ethyl acetate and dried, affording the product as a whitesolid (30 g.) pure by t.l.c.

NMR (DMSOd₆): δ = 2.0(s) 3H; 3.4(s) 2H; 3.7(s) 3H; 4.3(d) 2H; 4.9(d) 2H;5.0(m) 4H; 5.4(q) 1H and 7.0(m) 9H.

In a similar manner is prepared7-benzyloxycarboxamido-3-(1-methyltetrazol-5-ylthiomethyl)-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem.

NMR (CDCl₃): δ = 7.4(s) 5H; 7.1(q) 4H; 7.7(m) 2H; 5.25(s) 2H; 5.45(d)1H; 4.5(m) 4H; 4.0(s) 3H; 5.9(s) 3H and 5.79(s) 2H; and

7-benzyloxycarboxamido-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-[N-(p-methoxybenzyl)carbamoyl]-Δ³-cephem.

EXAMPLE 51

Starting with the appropriate 3-substituted-7-benzyloxycarboxamido-Δ³-cephem-4-carboxylic acid from Example 49, and employing the proceduresof Example 50, the following amide intermediates are prepared:

    ______________________________________                                         ##STR45##                                                                              R.sub.2         A                                                   ______________________________________                                        4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                                                  CH.sub.3 CO.sub.2                                     3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                                                      CH.sub.3 CO.sub.2                                     3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       CH.sub.3 CO.sub.2                                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                                                 CH.sub.3 CO.sub.2                                     3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                                        CH.sub.3 CO.sub.2                                     4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                CH.sub.3 CO.sub.2                                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                                              CH.sub.3 CO.sub.2                                     4-HOC.sub.6 H.sub.4 CH.sub.2                                                                          CH.sub.3 CO.sub.2                                     3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                                              CH.sub.3 CO.sub.2                                     2-furylmethyl-          CH.sub.3 CO.sub.2                                     1-(2-furyl)ethyl-       CH.sub.3 CO.sub.2                                     3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                                                 C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                   C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                                                       C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                                                       C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                                                     C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                                                     C.sub.2 H.sub.3 N.sub.4 S.sup.+                       2-Br-4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                                             C.sub.2 H.sub.3 N.sub. 4 S.sup.+                      4-HOC.sub.6 H.sub.4 CH(φ)                                                                         C.sub.2 H.sub.3 N.sub.4 S.sup.+                       5-methyl-2-furylmethyl- C.sub.2 H.sub.3 N.sub.4 S.sup.+                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                                                  C.sub.2 H.sub.3 N.sub.4 S.sup.+                       3,4-(CH.sub.3 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                                                C.sub.2 H.sub.3 N.sub.4 S.sup.+                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                C.sub.2 H.sub.3 N.sub.4 S.sup.+                       2-furylmethyl-          C.sub.2 H.sub.3 N.sub.4 S.sup.+                       5-methyl-2-thienylmethyl-                                                                             C.sub.2 H.sub.3 N.sub.4 S.sup.+                       ______________________________________                                         ##STR46##                                                                     ##STR47##                                                                

Phosphorous pentachloride (4.2 g., 20 mmole) is added to a suspension of7-benzyloxycarboxamido-3-acetoxymethyl-4-[N-(p-methoxybenzyl)carbamoyl]-.DELTA.³-cephem (5.3 g., 10 mmole) in dry, ethanol-free chloroform (100 ml.)containing pyridine (1.7 g., 20 mmole). After 30 min., NMR indicates thereaction is complete.

The solution is cooled in an ice-bath and a solution oftetramethylguanidinium azide (16.0 g., 100 mmole) in dry, ethanol freechloroform is added dropwise over a period of 20 min. After a further 10min. the ice-bath is removed and stirring is continued for 30 min. atambient temperatures. The solution is washed with water, sodiumbicarbonate solution (3 x), 6N hydrochloric acid (3 x), water, and driedover magnesium sulphate. Evaporation of the solvent affords the crudeproduct as a brown solid (3.7 g.), which is purified by columnchromatography on silica. Elution with dichloromethane: hexane (1:1) andthen with ether:dichloromethane:hexane (2:1:1)removes impurities.Elution with ether affords the product,7-benzyloxycarboxamido-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem, as a white solid, pure by t.l.c.

NMR (DMSOd₆): δ = 1.9(s) 3H; 3.65(s) 2H; 3.8(s) 3H; 4.3(s) 2H; 5.15(s)2H; 5.35(d) 1H; 5.6(m) 3H; 7.2(m) 9H and 8.6(d) 1H.

Similarly is prepared7-benzyloxycarboxamido-3-(1-methyltetrazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem.

NMR (DMSOd₆): δ = 7.3(s) 5H; 7.05(q) 4H; 6.5(s) 3H; 6.2(d) 1H; 5.05(s)2H; 3.85(s) 3H; 3.7(s) 3H; 3.5-4(m) 2H and 3.3(s) 2H.

EXAMPLE 53

Employing the procedure of Example 52, and starting with the amides ofExample 51, the following tetrazole intermediates are synthesized:

    ______________________________________                                         ##STR48##                                                                              R.sub.11        A                                                   ______________________________________                                        4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                                                  CH.sub.3 CO.sub.2                                     3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                                                      CH.sub.3 CO.sub.2                                     3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       CH.sub.3 CO.sub.2                                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                                                 CH.sub.3 CO.sub.2                                     3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                                        CH.sub.3 CO.sub.2                                     4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                CH.sub.3 CO.sub.2                                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                                              CH.sub.3 CO.sub.2                                     4-HOC.sub.6 H.sub.4 CH.sub.2                                                                          CH.sub.3 CO.sub.2                                     3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                                              CH.sub.3 CO.sub.2                                     2-furylmethyl-          CH.sub.3 CO.sub.2                                     1-(2-furyl)ethyl-       CH.sub.3 CO.sub.2                                     3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                                                 C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                   C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                                                       C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                                                       C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                                                     C.sub.3 H.sub.3 N.sub.2 S.sub.2 *                     4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                                                     C.sub.2 H.sub.3 N.sub.4 S.sup.+                       2-Br4-CH.sub.3 OC.sub.6 H.sub. 3 CH.sub.2                                                             C.sub.2 H.sub.3 N.sub.4 S.sup.+                       4-HOC.sub.6 H.sub.4 CH(φ)                                                                         C.sub.2 H.sub.3 N.sub.4 S.sup.+                       5-methyl-2-furylmethyl- C.sub.2 H.sub.3 N.sub.4 S.sup.+                       4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                                                  C.sub.2 H.sub.3 N.sub.4 S.sup.+                       3,4-(CH.sub.3 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                                                C.sub.2 H.sub.3 N.sub.4 S.sup.+                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                C.sub.2 H.sub.3 N.sub.4 S.sup.+                       2-furylmethyl-          C.sub.2 H.sub.3 N.sub.4 S.sup.+                       5-methyl-2-thienylmethyl-                                                                             C.sub.2 H.sub.3 N.sub.4 S.sup.+                       ______________________________________                                         ##STR49##                                                                     ##STR50##                                                                       EXAMPLE 54 7-Amino-3acetoxymethyl-4-(tetrazol-5-yl)-Δ.sup.3      

7-Benzyloxycarboxamido-3-acetoxymethyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem (100 mg.) is dissolved in trifluoroacetic acid/anisole (4:1,v/v), (0.5 cc) and to this reddish-brown solutiontrifluoromethanesulphonic acid is added from a Pasteur pipette (25drops). Immediate effervescence is observed as the solution turnscherry-red.

After 3 min. at room temperature the reaction mixture is quenched byaddition of ether (sodium dried). A brown gum is deposited, thesupernatent liquids are decanted, and the residue washed again withether.

The viscous gum is redissolved in the minimum volume of methylenechloride containing 1% triethylamine and the solution chromatographed onsilica (2 mm, 20 × 20, Kieselgel G F254) using acetonitrile/water (6:1v/v) as the eluting solvent.

The band at r.f. 0.4 was removed and extracted with 1%triethylamine/methylene chloride (3 × 150 ml.). The organic extracts areevaporated to dryness in vacuo to afford a white solid, a mixture of7-amino-3-acetoxymethyl-4-(tetrazol-5-yl)-Δ³ -cephem and triethylaminehydrochloride.

NMR (CDCl₃): δ = 5.25(d) 1H; 4.9(m) 2H and 2.05(s) 3H.

EXAMPLE 557-Amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ³ -cephem

In a manner similar to Example 54, starting with7-benzyloxycarboxamido-3-(1-methyltetrazol-5-ylthiomethyl)-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ³-cephem, the crude product is obtained.

The Zwitterion is isolated by crystallization of the crude reactionmixture, after precipitation with dry ether, from a minimum volume ofpotassium hydrogen phosphate pH 7 buffer. After initial dissolution ofthe crude reaction mixture the Zwitterion precipitates as a cream-yellowsolid and is pure by thin layer chromatography.

NMR (DMSOd₆): δ = 5.1(d) 1H; 4.8(d) 1H; 4.3(q) 2H; 3.9(s) 3H and 3.7(s)2H.

EXAMPLE 56

Employing the experimental conditions of Example 54, and starting withthe requisite products of Example 53, the intermediates7-amino-3-acetoxy-4-(tetrazol-5-yl)-Δ³ -cephem,7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ.sup.3-cephem and7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-.DELTA.³-cephem are produced.

EXAMPLE 57 7-(2',2', 2'-Trichloroethoxycarboxamido)-3-methyl-Δ²-cephem-4-carboxylic acid

7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-Δ³ -cephem-4-carboxylicacid (66.6 g.) and N-hydroxysuccinimide (21.6 g.) in dioxane (200 ml.)at room temperature is treated with dicyclohexylcarbodiimide (35.6 g.)and the mixture allowed to stir for 1 hour at room temperature. Themixture is filtered and the filtrate evaporated under reduced pressureto leave an oil which is dissolved in pyridine (400 ml.) at 7° C. and isthen treated with aqueous sodium hydroxide (7.5 g. in 100 ml.) withvigorous stirring. The mixture is allowed to warm to 25° C. and stirringcontinued for a further 1.75 hrs. The pyridine is evaporated underreduced pressure and the residue poured onto ice. The pH is adjusted to2 with 6N HCl acid and the precipitate extracted into ethyl acetate. Theorganic solution is washed with 1N HCl acid, water, and then evaporatedunder reduced pressure. The residue is dissolved in aqueous sodiumcarbonate solution and the resultant solution is washed with ethylacetate. The aqueous solution is treated with charcoal, filtered and thepH of the filtrate adjusted to 2 with 6N HCl acid. The precipitate isextracted into ethyl acetate and the organic solution is treated withcharcoal, filtered, and dried (MgSO₄). The solution is then evaporatedunder reduced pressure to leave the required product as a foam, whichsolidifies on trituration with petroleum ether (48.0 g.) and isessentially pure by chromatography.

NMR (CDCl₃): δ = 7.5(d) 1H; 6.0(q) 1H; 5.2(m) 2H; 4.7(s) 2H; 4.6(s) 1Hand 1.9(s) 3H.

EXAMPLE 58

In a similar manner to Example 57, starting with7-(2',2',2'-tribromoethoxycarboxamido)-3-methyl-Δ³ -cephem-4-carboxylicacid prepared by the general procedure of Example 1A, in place of thecorresponding chloro compound,7-(2',2',2'-tribromoethoxycarboxamido)-3-methyl-Δ² -cephem-4-carboxylicacid is produced.

EXAMPLE 597-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ²-cephem

7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-Δ² -cephem-4carboxylicacid (46.0 g.) and N-hydroxysuccinimide (14.3 g.) in dioxane (750 ml.)is treated after 1 hr. with dicylohexylcarbodiimide (24.3 g.) at roomtemperature with stirring. To this stirred solution is addedp-methoxybenzylamine (32.8 g.) in dioxane (200 ml.) and the mixturestirred for a further hour at room temperature. The mixture is filteredand the solution stirred for a further hour at room temperature. Themixture is filtered and the solution concentrated to 300 ml. underreduced pressure. The concentrate is poured into a saturated aqueous Na₂CO₃ solution (2 liters) and the precipitate collected. The precipitateis washed with water, 1N HCl, and finally water. The solid is driedunder reduced pressure at 100° C. for 16 hrs. to furnish7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)-carbamoyl]-Δ²-cephem (58.6 g.). A sample is recrystallized from acetone (m.p.219°-220° C.).

NMR (DMSOd₆): δ = 7.0(q) 4H; 6.0(q) 1H; 5.2(m) 2H; 4.7(s) 2H; 4.6(s) 1H;4.2(d); 2H; 3.7(s) 3H and 1.7(s) 3H.

EXAMPLE 60

Starting with 7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-Δ²-cephem-4-carboxylic acid, prepared by the procedure of Example 57, andthe appropriate amine, and repeating the procedure of Example 59, thefollowing intermediate amides are prepared: ##STR51##

EXAMPLE 61

Similarly, when 7-(2',2',2'-tribromoethoxycarboxamido)-3-methyl-Δ²-cephem-4-carboxylic acid is employed as the reagent in place of7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-Δ² -cephem-4-carboxylicacid in the procedure of Example 59 along with the appropriate amine,the following amides are synthesized:

    ______________________________________                                         ##STR52##                                                                                 R.sub.2                                                          ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-C.sub.2 H.sub.5 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                           3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3-Cl4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                              4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      2-F-HOC.sub.6 H.sub.3 CH.sub.2                                                3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 627-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[1-(p-methoxybenzyl)-tetrazol-5-yl]-Δ²-cepem

7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[N-(p-methoxybenzyl)carbamoyl]-Δ²-cephem (44.2 g.) and pyridine (14.06 g.) in chloroform (300 ml.,ethanol free) at 40° C. is treated with phosphorus pentachloride (27.5g.) and the mixture stirred at 40° C. for 3 hrs. The solution is cooledto room temperature and tetramethylguanidinium azide (87.9 g.) added,and the solution allowed to stir at room temperature for 2 hrs. Thesolution is then washed with water, aqueous sodium bicarbonate, 1N HClacid, water, and dried (MgSO₄). The organic solution is evaporated underreduced pressure to leave a gum which is dissolved in ethyl acetate (200ml.) and passed down a column of alumina. The fraction containing therequired product is collected and the solution evaporated to drynessunder reduced pressure to yield the product as a pale orange solid (42.4g.).

NMR (CDCl₃): δ = 7.0(q) 4H; 6.1(d) 1H; 6.0(s) 1H; 5.6(q) 2H; 5.4(s) 1H;5.2(q) 1H; 4.8(d) 1H; 4.7(s) 2H; 3.7(s) 3H and 1.5(s) 3H.

EXAMPLE 63

In a manner similar to the procedure of Example 62, the amides ofExample 60 are converted to the corresponding tetrazoles of thestructure:

    ______________________________________                                         ##STR53##                                                                                 R.sub.11                                                         ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(CH.sub.3)                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(φ)                                         2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-CH.sub.3 OC.sub.6 H.sub.4 CH(n-C.sub.3 H.sub.7)                             3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                4-C.sub.2 H.sub.5 CO.sub.2 H.sub.4 CH.sub.2                                   3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               4-HOC.sub.6 H.sub.4 CH(φ)                                                 3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3-CH.sub.3 O4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                      4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                      3-Cl4-C.sub.6 H.sub.4 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)             2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              5-methyl-2-thienylmethyl-                                                     1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 64

Employing the procedure of Example 62, and starting with the requisitereagents and the appropriate amide from Example 61, the followingtetrazole intermediates are synthesized:

    ______________________________________                                         ##STR54##                                                                                 R.sub.11                                                         ______________________________________                                               4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.4 CH.sub.2                          4-C.sub.6 H.sub.5 CH.sub.2 O3-FC.sub.6 H.sub.3 CH.sub.2                       2-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      4-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              2-Br4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                      2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH(CH.sub.3)                           4-C.sub.2 H.sub.5 CO.sub.2 H.sub.4 CH.sub.2                                   3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                3-F4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                               3-I4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       4-(i-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        3,4-(C.sub.6 H.sub.5 CH.sub.2 O).sub.2 C.sub.6 H.sub.3 CH.sub.2               4-CH.sub.3 OC.sub.6 H.sub.4 CH(CH.sub.3)                                      4-CH.sub.3 OC.sub.6 H.sub.4 CH(C.sub.2 H.sub.5)                               3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2                               3-F4-CH.sub.3 OC.sub.6 H.sub.3 CH.sub.2                                       3-Cl4-CH.sub.3 OC.sub.6 H.sub.3 CH(CH.sub.3)                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-HOC.sub.6 H.sub.4 CH.sub.2                                                  4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                  3-Cl4-HOC.sub.6 H.sub.3 CH.sub.2                                              3-Cl4-CH.sub.3 CO.sub.2 C.sub.6 H.sub.3 CH.sub.2                              4-C.sub.6 H.sub.2 OC.sub.6 H.sub.3 CH(CH.sub.3)                               3-Cl4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6 H.sub.3 CH.sub.2                      2-F4-HOC.sub.6 H.sub.3 CH.sub.2                                               3,4-(C.sub.2 H.sub.5 CO.sub.2).sub.2 C.sub.6 H.sub.3 CH.sub.2                 4-(n-C.sub.3 H.sub.7 CO.sub.2)C.sub.6 H.sub.4 CH.sub.2                        2-furylmethyl-                                                                5-methyl-2-furylmethyl-                                                       2-thienylmethyl-                                                              1-(2-furyl)ethyl-                                                             1-(5-methyl-2-furyl)ethyl-                                             ______________________________________                                    

EXAMPLE 657-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-Δ.sup.2-cephem

7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-[1-(p-methoxybenzyl)tetrazol-5-yl]-Δ²-cephem (40.7 g.) in trifluoroacetic acid (280 ml.) containing anisole(70 ml.) is allowed to stand at 50° C. for 6 hrs. The solution is pouredinto water (1 liter) and the suspension extracted with ethyl acetate.The organic solution is extracted with saturated aqueous sodiumbicarbonate and the aqueous solution is adjusted to pH 2 with IN HClacid, and the precipitate extracted into ethyl acetate. The organicsolution is dried (MgSO₄) and evaporated under reduced pressure to give7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-Δ²-cephem as a pale brown solid (23.2 g.). A sample is recrystallized fromchloroform (ethanol free) m.p. 165°-167° C.

NMR (DMSOd₆): δ = 6.4(q) 1H; 5.8(s) 1H; 5.2(m) 2H; 4.8(s) 2H and 1.8(s)3H.

EXAMPLE 66

The procedure of Example 65 is repeated, starting with the reagents ofExample 63, to produce 7-(2', 2',2'-trichloroethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-Δ² cephem,identical with that formed in Example 65.

EXAMPLE 67

Starting with the intermediates of Example 64, and following theprocedure of Example 65,7-(2',2',2'-tribromoethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-Δ.sup.2cephem is formed.

EXAMPLE 687-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem

To a suspension of7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-(tetrazol-5-yl)-Δ²-cephem (8.27 g.) in methylene chloride (50 ml.) is added in turn,triethylamine (2.22 g.) and chloromethyl methyl ether (1.76 g.) and thesolution stirred at room temperature for 30 min. The solution is thenwashed with water, aqueous sodium bicarbonate, and dried (MgSO₄).Evaporation under reduced pressure gives7-(2',2',2'-trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (7.3 g.) as a cream solid.

NMR (CDCl₃): δ = 6.4(d) 1H; 6.0(q) 1H; 5.8(s) 2H; 4.7(s) 2H; 3.4(m) 3Hand 1.7(s) 3H.

EXAMPLE 69

Employing the appropriate tetrazole of Example 65 or 66 and therequisite alkyl halide, and repeating the procedure of Example 68, thefollowing mixture of compounds is formed:

    ______________________________________                                         ##STR55##                                                                    and                                                                            ##STR56##                                                                           R             R.sub.11 /R.sub.1                                        ______________________________________                                               Br.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 OCH.sub.2                                              Br.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 CO.sub.2 CH.sub.2                                      Br.sub.3 CCH.sub.2 OCO                                                                      C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 CO.sub.2 CH(CH.sub.3)                                  Br.sub.3 CCH.sub.2 OCO                                                                      (CH.sub.3)hd 2CHCO.sub.2 CH.sub.2                               Br.sub.3 CCH.sub.2 OCO                                                                      C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                           Br.sub.3 CCH.sub.2 OCO                                                                      (CH.sub.3).sub.3 CCO.sub.2 CCH.sub.2                            Br.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 (CH.sub.2).sub.2 CO.sub.2 CH.sub.2                     Br.sub.3 CCH.sub.2 OCO                                                                      (CH.sub.3).sub.3 CCO.sub.2 CH(CH.sub.3)                         Br.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.3                     Br.sub.3 CCH.sub.2 OCO                                                                      (CH.sub.3).sub.2 CHCH.sub.2 CO.sub.2 CH.sub.2                   Br.sub.3 CCH.sub.2 OCO                                                                      C.sub.8 H.sub.5 O.sub.2*                                        Cl.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 CO.sub.2 CH.sub.2                                      Cl.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 CO.sub.2 CH(CH.sub.3)                                  Cl.sub.3 CCH.sub.2 OCO                                                                      A C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                             Cl.sub.3 CCH.sub.2 OCO                                                                      C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                           Cl.sub.3 CCH.sub.2 OCO                                                                      (CHhd 3).sub.3 CCO.sub.2 CH.sub.2                               Cl.sub.3 CCH.sub.2 OCO                                                                      (CH.sub.3).sub.2 CHCO.sub.2 CH.sub.2                            Cl.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                     Cl.sub.3 CCH.sub.2 OCO                                                                      CH.sub.3 (CH.sub.2).sub.3 CO.sub. 2 CH(CH.sub.3)                Cl.sub.3 CCH.sub.2 OCO                                                                      (CH.sub.3).sub.2 CHCH.sub.2 CO.sub.2 CH.sub.2                   Cl.sub.3 CCH.sub.2 OCO                                                                      C.sub.8 H.sub.5 O.sub.2*                                 ______________________________________                                         ##STR57##                                                                       EXAMPLE 70 7-(2',2',2'-Trichloroethoxycarboxamido)-3-(1-methyltetrazol-

7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (8.0 g.) in carbon tetrachloride (160 ml.) and chloroform (16ml.) was deoxygenated. N-Bromosuccinimide (3.20 g.) and benzoyl peroxide(200 mg.) is added and the stirred mixture at 10°-15° C. illuminated(250 watt, tungsten lamp) for 2 hrs. During this time additionalchloroform is added to maintain a clear supernatant, and a furtheramount of benzoyl peroxide (200 mg.) added 30 min. after the start ofillumination.

The succinimide is filtered off and the filtrate treated with thetriethylamine salt of 5-mercapto-1-methyltetrazole (3.40 g.) for 2.5hrs. at 45° C. The organic solution is then washed with water, aqueoussodium bicarbonate, water and finally dried (MgSO₄). The organicsolution is evaporated to dryness under reduced pressure. The residue ispurified by means of column chromatography (Silica gel; ethylacetate;light petroleum ether, 1:1) to give the desired product (3.0g.).

NMR (CDCl₃): δ = 6.6(s) lH; 6.2(d) 1H; 6.0(s) lH; 5.9(s) 2H; 5.4(m) 2H;4.8(s) 2H; 4.2(q) 2H; 4.0(s) 3H and 3.5(s) 3H.

EXAMPLE 717-(2',2',2'-Trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-methoxymethyltetrazol-5-yl)-Δ²-cephem

7-(2',2',2'-Trichloroethoxycarboxamido)-3-methyl-4-(methoxymethyltetrazol-5-yl)-Δ² -cephem (4.0 g.) in carbontetrachloride (60 ml.) and chloroform (8 ml.) is treated with N-bromosuccinimide and benzoyl peroxide as in Example 70. The product issimilarly treated with the triethylamine salt of5-mercapto-2-methylthiadiazol (2 g.) to give, after columnchromatography (silica, ethyl acetate/light petroleum ether 1:1),7-(2',2',2'-trichloroethoxycarboxamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (1.1 g.).

NMR (CDCl₃): δ = 6.6(s) lH; 6.3(d) lH; 6.1(s) 1H; 5.9(s) 2H; 5.3-5.7 (m)2H; 4.8(s) 2H; 4.1(q) 2H; 3.5(s) 3H and 2.7(s) 3H.

EXAMPLE 72

Following the procedure of Example 70 or 71, and starting with therequisite Δ² -cephems from Example 68 and Example 69, and theappropriate mercapten, the following compounds are formed:

    ______________________________________                                         ##STR58##                                                                    and                                                                            ##STR59##                                                                    R              R.sub.11 /R.sub.1                                                                              A                                             ______________________________________                                        Cl.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 CO.sub.2 CH.sub.3                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2*                 Cl.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                                  C.sub.2 H.sub.3 N.sub.2 S.sub.2*                 Cl.sub.3 CCH.sub.2 OCO                                                                   C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.2 S.sub.2*                 Cl.sub.3 CCH.sub.2 OCO                                                                   (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                             C.sub.2 H.sub.3 N.sub.2 S.sub. 2*                Cl.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH(CH.sub.3)                                                 C.sub.2 H.sub.3 N.sub.2 S.sub.2*                 Cl.sub.3 CCH.sub.2 OCO                                                                   C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.2 S.sub.2*                 Cl.sub.3 CCH.sub.2 OCO                                                                   (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                             C.sub.2 H.sub.3 N.sub.2 S.sup.+                  Cl.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 CO.sub.2 CH.sub.2                                                                      C.sub.2 H.sub.3 N.sub.2 S.sup.+                  Cl.sub.3 CCH.sub.2 OCO                                                                   .sup.# C.sub.8 H.sub.5 O.sub.2                                                                  C.sub.2 H.sub.3 N.sub.2 S.sup.+                  Cl.sub.3 CCH.sub.2 OCO                                                                   C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.2 S.sup.+                  Cl.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                                  C.sub.2 H.sub.3 N.sub.2 S.sup.+                  Br.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 OCH.sub.2                                                                              C.sub.3 H.sub.3 N.sub.2 S.sub.2*                 Br.sub.3 CCH.sub. 2 OCO                                                                  CH.sub.3 CO.sub.2 CH.sub.2                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2*                 Br.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                                  C.sub.3 H.sub.3 N.sub.2 S.sub.2*                 Br.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 (CH.sub.2)CO.sub.2 CH.sub.2                                                            C.sub.3 H.sub.3 N.sub.2 S.sub.2*                 Br.sub.3 CCH.sub.2 OCO                                                                   (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                             C.sub.3 H.sub.3 N.sub.2 S.sub.2*                 Br.sub.3 CCH.sub.2 OCO                                                                   (CH.sub.3).sub.2 CHCH.sub.2 CO.sub.2 CH.sub.2                                                   C.sub.3 H.sub.3 N.sub.2 S.sub.2*                 Br.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 OCH.sub.2                                                                              C.sub.2 H.sub.3 N.sub.4 S.sup.+                  Br.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH(CH.sub.3)                                                 C.sub.2 H.sub.3 N.sub.4 S.sup.+                  Br.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                                  C.sub.2 H.sub.3 N.sub.4 S.sup.+                  Br.sub.3 CCH.sub.2 OCO                                                                   (CH.sub.3 CCO.sub.2 CH.sub. 2                                                                   C.sub.2 H.sub.3 N.sub.4 S.sup.+                  Br.sub.3 CCH.sub.2 OCO                                                                   CH.sub.3 CO.sub.2 CH.sub.2                                                                      C.sub.2 H.sub.3 N.sub.4.sup.+                    Br.sub.3 CCH.sub.2 OCO                                                                   C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.4 S.sup.+                  Br.sub.3 CCH.sub.2 OCO                                                                   .sup.# C.sub.8 H.sub.5 O.sub.2                                                                  C.sub.2 H.sub.3 N.sub.4 S.sup.+                  ______________________________________                                         ##STR60##                                                                     ##STR61##                                                                     ##STR62##                                                                

7(2',2',2'-Trichloroethoxycarboxamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (2.0 g.) in acetic acid-water mixture (7:3, 20 ml.) at 0° C. istreated with activated zinc dust (2.0 g.) with stirring. After 1 hourthe mixture is filtered and the filtrate diluted with water (100 ml.)The pH of the mixture was adjusted to 2 with 1N HCl acid and then washedtwice with ethyl acetate. The pH of the clear aqueous solution isadjusted to 6 with sodium bicarbonate and the mixture extracted withchloroform. The organic solution is washed with pH 7 buffer, dried(MgSO₄), and, finally evaporated under reduced pressure to leave7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (0.9 g.) as a foam, pure by chromatography.

NMR (CDCl₃): δ = 6.6(s) lH; 5.95(s) lH; 5.85(s) 2H; 5.25(d) lH; 4.70(d)lH; 4.1(q) 2H; 3.95(s) 3H and 3.5(s) 3H.

In a similar manner is prepared7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem.

NMR (CDCl₃): δ = 6.8(s) lH; 6.4(s) lH; 6.0(s) 2H; 5.4(d) lH; 4.8(d) lH;4.2(q) 2H; 3.7(s) 3H and 3.2(s) 2H.

EXAMPLE 74

By substituting the appropriate compound of Example 69 for the Δ²-cephem of Example 73, and following the experimental procedure ofExample 73, the following 7-amino-Δ² -cephems are formed:

    ______________________________________                                         ##STR63##                                                                    and                                                                            ##STR64##                                                                              R.sub.11 /R.sub.1                                                   ______________________________________                                               CH.sub.3 OCH.sub.2                                                            CH.sub.3 CO.sub.2 CH.sub.2                                                    CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                C.sub.2 H.sub.5 CO.sub.2 CH.sub.3                                             C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                                         (CH.sub.3).sub.2 CHCO.sub.2 CH.sub.2                                          (CH.sub.3).sub.3 CO.sub.2 CH.sub.2                                            CH.sub.3 (CH.sub.2).sub.2 CO.sub.2 CH.sub.2                                   CH.sub.3 (CH.sub.2l ).sub.3 CO.sub.2 CH(CH.sub.3)                             *C.sub.8 H.sub.5 O.sub.2                                                      (CH.sub.3).sub.2 CHCH.sub.2 CO.sub.2 CH.sub.2                                 (CH.sub.3).sub.3 CCO.sub.2 CH(CH.sub.3)                                ______________________________________                                         ##STR65##                                                                

The procedure of Example 73 is again repeated, starting with theappropriate Δ² -cephems of Example 72, to give the following congeners:

    ______________________________________                                         ##STR66##                                                                    and                                                                            ##STR67##                                                                              R.sub.11 /R.sub.1                                                   ______________________________________                                               CH.sub.3 CO.sub.2 CH.sub.2                                                    CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                             (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                           CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH(CH.sub.3)                               C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                             (CH.sub.3).sub.2 CHCH.sub.2 CO.sub.2 CH.sub.2                          ______________________________________                                    

EXAMPLE 76

Again, the procedure of Example 73, applied to the requisite compoundsof Example 72, provides the following intermediates:

    ______________________________________                                         ##STR68##                                                                    and                                                                            ##STR69##                                                                                 R.sub.11 /R.sub.1                                                ______________________________________                                                 (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                           CH.sub.3 CO.sub.2 CH.sub.2                                                    *C.sub.8 H.sub.5 O.sub.2                                                      C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                             CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH(CH.sub.3)                      ______________________________________                                         ##STR70##                                                                      EXAMPLE 77 7-(Tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylt

A.7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem

7-Amino-3-(2-methyl-1,3,4,-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (430 mg.) and tetrazol-1-yl acetic acid (133 mg.) intetrahydrofuran (10 ml.) and acetonitrile (10 ml.) is treated withdicyclohexylcarbodimide (215 mg.) and the mixture allowed to stand atroom temperature for 1 hr. The mixture is filtered and evaporated underreduced pressure to leave7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (520 mg.) as a cream solid, pure by thin layer chromatography.

NMR (CDCl₃): δ = 9.1(s) 1H; 6.6(s) 1H; 6.0(s) 1H; 5.9(s) 2H; 5.4(s) 2H;5.4(s) 1H; 5.2(d) 1H; 4.0(q) 2H; 3.4(s) 3H and 2.6(s) 3H.

b.7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem 1-oxide.

7-(Tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (500 mg.) in chloroform (20 ml.) is treated withm-chloroperbenzoic acid (219 mg.) at 0° C. with stirring. After 1 hr. at0° C. pyridine is added (40 mg.) and the mixture allowed to warm to roomtemperature. After a further hour the mixture is concentrated underreduced pressure and diethyl ether added to the concentrate. The creamsolid which precipitates is collected, dried under reduced pressure andthe required product (410 mg.) is obtained as a cream solid, pure bychromatography.

NMR (DMSOd₆ /acetone d₆): δ = 8.9(s) 1H; 6.0(s) 2H; 6.0, 1H; 5.6(s) 2H;5.2(d) 1H; 4.5(q) 2H; 4.0(s) 2H; 3.5(s) 3H and 2.7(s) 3H.

c.7-(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem7-(Tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem 1-oxide (400 mg.) in dimethylformamide (10 ml.) is treated withanhydrous stannous chloride (400 mg.) and acetyl chloride (200 mg.) at0° C. with stirring. The mixture is allowed to stir for 1 hour and isthen poured into an excess of water. The aqueous mixture is extractedseveral times with chloroform, and the organic solution washed severaltimes with water. The chloroform solution is dried (MgSO₄) andevaporated under reduced pressure to give the required compound as afoam (250 mg.), pure by thin layer chromatography.

NMR (CDCl₃): δ = 9.0(s) 1H; 8.7(d) 1H; 6.0(s) 2H; 6.0, 1H; 5.4(s) 2H;5.2(d) 1H; 4.4(q) 2H; 3.7(s) 2H; 3.4(s) 3H and 2.7(s) 2H.

d.7(tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ³-cephem

7-(Tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³cephem (70 mg.) in trifluoroacetic acid (2 ml.) and anisole (0.5 ml.) isallowed to stand at 20° C. for 6 hrs. After this time thetrifluoroacetic acid is removed under reduced pressure to leave an oil.This residue is diluted with ethyl acetate and the resulting organicsolution extracted with saturated aqueous sodium bicarbonate solution.The aqueous solution is acidified to pH 2 with 2N HCl acid and thesolution extracted with ethyl acetate. The organic solution is dried(MgSO₄) and evaporated under reduced pressure to leave an oil whichcrystallizes on addition of diethyl ether, to give the required productas colorless needles (35 mg.), pure by chromatography.

NMR (trifluoroacetic acid-d): δ = 9.5(s) 1H; 5.8(d) 1H; 5.5(s) 2H;5.2(d) 1H; 4.5(s) 2H; 3.6(s) 2H and 2.8(s) 3H.

EXAMPLE 78

Starting with the appropriate methoxymethyl substituted Δ² -cephems ofExamples 73 and 74 and acids, and employing the procedure of Example77A-D, the following compounds are synthesized:

    ______________________________________                                         ##STR71##                                                                    Ar             Q        n        A                                            ______________________________________                                        C.sub.6 H.sub.5                                                                              --       0       H                                             2-ClC.sub.6 H.sub.4                                                                          --       0       H                                             4-ClC.sub.6 H.sub.4                                                                          --       0       H                                             2,3-Cl.sub.2 C.sub.6 H.sub.3                                                                 --       0       C.sub.2 H.sub.3 N.sub.4 S*                    3,4-Cl.sub.2 C.sub.6 H.sub.3                                                                 --       0       C.sub.2 H.sub.3 N.sub.4 S*                    3-FC.sub.6 H.sub.4                                                                           --       0       C.sub.2 H.sub.3 N.sub.4 S*                    4-FC.sub.6 H.sub.4                                                                           --       0       C.sub.2 H.sub.3 N.sub.4 S*                    3,5-F.sub.2 C.sub.6 H.sub.3                                                                  --       0       C.sub.2 H.sub.3 N.sub.4 S*                    4-BrC.sub.6 H.sub.4                                                                          --       0       C.sub.2 H.sub. 3 N.sub.4 S*                   3,4-Br.sub.2 C.sub.6 H.sub.3                                                                 --       0       C.sub.2 H.sub.3 N.sub.4 S*                    3-HOC.sub.6 H.sub.4                                                                          --       0       C.sub.2 H.sub.3 N.sub.4 S*                    4-HOC.sub.6 H.sub.4                                                                          --       0       C.sub.2 H.sub.3 N.sub.4 S*                    4-CH.sub.3 C.sub.6 H.sub.4                                                                   --       0       C.sub.2 H.sub.3 N.sub.4 S*                    3-Cl4-HOC.sub.6 H.sub.3                                                                      --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-F4-HOC.sub.6 H.sub.3                                                                       --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         4-CH.sub.3 OC.sub.6 H.sub.4                                                                  --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-Br4-CH.sub.3 OC.sub.6 H.sub.3                                                              --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-CH.sub.34-HOC.sub.6 H.sub.3                                                                --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-CH.sub.34-ClC.sub.6 H.sub.3                                                                --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         2-thienyl      --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-thienyl-     --       0       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         2-ClC.sub.6 H.sub.4                                                                          N.sub.3  1       H                                             4-ClC.sub.6 H.sub.4                                                                          N.sub.3  1       H                                             2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                 N.sub.3  1       H                                             4-FC.sub.6 H.sub.4                                                                           N.sub.3  1       H                                             3,5-F.sub.2 C.sub.6 H.sub.3                                                                  N.sub.3  1       C.sub.2 H.sub.3 N.sub.4 S*                    4-BrC.sub.6 H.sub.4                                                                          N.sub.3  1       C.sub.2 H.sub.3 N.sub.4 S*                    4-HOC.sub.6 H.sub.4                                                                          N.sub.3  1       C.sub.2 H.sub.3 N.sub.4 S*                    3-HOC.sub.6 H.sub.4                                                                          N.sub.3  1       C.sub.2 H.sub.3 N.sub.4 S *                   4-CH.sub.3 OC.sub.6 H.sub.4                                                                  N.sub.3  1       C.sub.2 H.sub.3 N.sub.4 S*                    3-F4-HOC.sub.6 H.sub.3                                                                       N.sub.3  1       C.sub.2 H.sub.3 N.sub.4 S*                    3-Cl4-HOC.sub.6 H.sub.3                                                                      N.sub.3  1       C.sub.2 H.sub.3 N.sub.4 S*                    3-Br4-CH.sub.3 OC.sub.6 H.sub.3                                                              N.sub.3  1       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         4-CH.sub.3 C.sub.6 H.sub.4                                                                   N.sub.3  1       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-Cl4-CH.sub.3 C.sub.6 H.sub.3                                                               N.sub.3  1       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         4-CH.sub.3 C.sub.6 H.sub.4                                                                   N.sub.3  1       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                        N.sub.3  1       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         2-thienyl-     N.sub.3  1       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         3-thienyl-     N.sub.3  1       C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         ______________________________________                                         ##STR72##                                                                     ##STR73##                                                                       EXAMPLE 79 7-D-(α-Hydroxy-α-phenylacetamido)-3-(1-methyltet

A.7-d-(α-formyloxy-α-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem

Starting with the appropriate reagents and following the procedure ofExample 77A, the desired intermediate is prepared.

NMR (CDCl₃): δ = 8.2(s) 1H; 7.3(s) 5H; 6.4(s) 1H; 6.2(s) 1H; 5.9(s) 1H;5.7(s) 2H; 5.5(8) 1H; 5.2(d) 1H; 4.0(q) 2H; 3.9(s) 3H and 3.4(s) 3H.

b.7-d-(α-formyloxy-α-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem 1-oxide

Employing the above intermediate from Example 79A and following theprocedure of Example 77B, the desired compound is isolated and used insubsequent reaction without further purification.

7-D-(α-Formyloxy-α-phenylacetamido)-3-(1-methylthiomethyl)-4-(methoxymethymethyltetrazol-5-yl)-Δ³-cephem

The procedure of Example 77C is employed, starting with the appropriatecompound from Example 79B, to give the desired product.

NMR (CDCl₃): δ = 8.3(s) 1H; 7.4(s) 5H; 6.3(s) 1H; 6.0(s) 2H; 6.0, 1H;5.2(d) 1H; 4.5(q) 2H; 4.0(s) 3H; 3.8(s) 2H and 3.5(s) 3H.

d.7-d-(α-formyloxy-α-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ³-cephem

The trifluoroacetic acid-anisole treatment of Example 77D is repeated,starting with the product of Example 79C, to provide the desiredproduct. NMR (acetone-d₆ /D₂ O): δ = 8.3(s) 1H; 7.5(m) 5H; 6.2(s) 1H;5.9(d) 1H; 5.3(d) 1H; 4.4(s) 2H and 4.0(HOD).

(acetone-d₆ /D₂ O/trifluoroacetic acid-d): δ = 4.4(s) 2H; 4.0(s) 3H and3.9(s) 2H.

e.7-d-(α-hydroxy-α-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ³-cephem

7-D-(α-Formyloxy-α-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ³-cephem (100 mg.) in aqueous sodium bicarbonate solution (5 ml.) isallowed to stand at room temperature for 3 hrs. The pH of the reactionmixture is adjusted to 2 to 2 with 2N HCl acid and extracted with ethylacetate. The organic solution is dried (MgSO₄) and evaporated underreduced pressure to leave the required product as a cream solid (35mg.), essentially pure by thin layer chromatography.

EXAMPLE 80

Again, starting with the requisite methoxymethyl substituted Δ² -cephemsof Examples 73 and 74 and the appropriately substitutedα-formyloxy-α-phenylacetic acid, and employing the procedure of Example77A-D, the following Δ³ -cephems are prepared:

    ______________________________________                                         ##STR74##                                                                    Ar            *(configuration)                                                                              A                                               ______________________________________                                        2-ClC.sub.6 H.sub.4                                                                         D              H                                                3-ClC.sub.6 H.sub.4                                                                         D              H                                                4-ClC.sub.6 H.sub.4                                                                         DL             H                                                2-FC.sub.6 H.sub.4                                                                          L              H                                                4-FC.sub.6 H.sub.4                                                                          D              C.sub.2 H.sub.3 N.sub.4 S*                       4-FC.sub.6 H.sub.4                                                                          L              C.sub.2 H.sub.3 N.sub.4 S*                       3-BrC.sub.6 H.sub.4                                                                         DL             C.sub.2 H.sub.3 N.sub.4 S*                       3-CH.sub.3 C.sub.6 H.sub.4                                                                  D              C.sub.2 H.sub.3 N.sub.4 S*                       4-CH.sub.3 C.sub.6 H.sub.4                                                                  DL             C.sub.2 H.sub.3 N.sub.4 S*                       4-CH.sub.3 OC.sub.6 H.sub.4                                                                 D              C.sub.2 H.sub.3 N.sub.4 S*                       4-CH.sub.3 OC.sub.6 H.sub.4                                                                 DL             C.sub.2 H.sub.3 N.sub.4 S *                      3-CH.sub.3 OC.sub.6 H.sub.4                                                                 D              C.sub.2 H.sub.3 N.sub.4 S*                       2-HOC.sub.6 H.sub.4                                                                         D              C.sub.2 H.sub.3 N.sub.4 S*                       3-HOC.sub.6 H.sub.4                                                                         D              C.sub.2 H.sub.3 N.sub.4 S*                       2-Cl-FC.sub.6 H.sub.3                                                                       D              C.sub.2 H.sub.3 N.sub.4 S*                       3-Cl4-FC.sub.6 H.sub.3                                                                      DL             C.sub.2 H.sub.3 N.sub.4 S*                       3-Cl4-BrC.sub.6 H.sub.3                                                                     L              C.sub.2 H.sub.3 N.sub.4 S*                       3,4-Br.sub.2 C.sub.6 H.sub.3                                                                D              C.sub.2 H.sub.3 N.sub.4 S*                       3-F4-CH.sub.3 C.sub.6 H.sub.3                                                               DL             C.sub.2 H.sub.3 N.sub.4 S*                       3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                       D              C.sub.2 H.sub.3 N.sub.4 S*                       3,4-(HO).sub.2 C.sub.6 H.sub.3                                                              D              C.sub.2 H.sub.3 N.sub.4 S*                       3-Cl4-HOC.sub.6 H.sub.3                                                                     L              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            2-F4-HOC.sub.6 H.sub.3                                                                      DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            2-F4-CH.sub.3 OC.sub.6 H.sub.3                                                              DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                      D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3-CH.sub.3 O4-HOC.sub.6 H.sub.3                                                             D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3-Br5-HOC.sub.6 H.sub.3                                                                     L              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3-CH.sub.34-HOC.sub.6 H.sub.3                                                               D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                       DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3-CH.sub.34-CH.sub.3 C.sub.6 H.sub.3                                                        D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            4-HOC.sub.6 H.sub.4                                                                         DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            4-HOC.sub.6 H.sub.4                                                                         D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3-CH.sub.3 C.sub.6 H.sub.4                                                                  D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            2,3-Cl.sub.2 C.sub.6 H.sub.3                                                                DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            3,5-Cl.sub.2 C.sub.6 H.sub.3                                                                D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+            ______________________________________                                         ##STR75##                                                                     ##STR76##                                                                       EXAMPLE 81 7-D-(α-Amino-α-phenylacetamido)-3-(1-methyltetra    zol-5-ylthiomethyl)-4-(tetrazol-5-yl)-Δ.sup.3 -cephem               

A.7-[d-α-(t-butoxycarbonylamino)-phenylacetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol)-5-yl)-Δ²-cephem

7-Amino-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (100 mg.) and N-t-butoxycarbonylphenylglycine (63.4 mg.) inethyl acetate-acetonitrile (1:1, 2 ml.) is treated withdicyclohexylcarbodiimide (52 mg.) at 15° C. After one hour the mixtureis filtered and the filtrate diluted with ethyl acetate (10 ml.) and theresulting solution washed with 1N HCl acid, aqueous bicarbonate, andfinally water. Drying (MgSO₄) and evaporation under reduced pressuregave the product (152 mg.) as a pale yellow solid.

NMR (CDCl₃): δ = 7.25(s) 5H; 6.5(s) 1H; 6.0(s) 1H; 5.8(s) 2H; 5.6(m) 2H;5.3(m) 2H; 4.1(q) 2H; 3.9(s) 3H; 3.5(s) and 1.4(s) 9H.

b.7-[d-α-(t-butoxycarbonylamino)phenylacetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem 1-oxide

7-[D-α-(t-butoxycarbonylamido)phenylacetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ²-cephem (140 mg., 0.22 mmole) in chloroform (2 ml.) is treated withm-chloroperbenzoic acid (51 mg., 85%) at 0° C. with stirring. Thesolution is kept at 0° C. for 1 hour and then pyridine (20 mg.) is addedand the solution allowed to warm to room temperature and is kept at thistemperature for a further 2 hrs.

The reaction mixture is diluted with chloroform and washed with 1N HClacid, aqueous sodium bicarbonate and dried (MgSO₄). Evaporation underreduced pressure gives the required product as a cream solid (120 mg.).

This material was used directly in the next reaction without furtherpurification.

C.7-[d-α-(t-butoxycarbonylamino)phenylacetamido]-3-(1-methyltetrazol-5-yl-thiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem

7-[D-α-(t-butoxycarboxylamino)phenylacetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem 1-oxide (120 mg.) is suspended in dimethylformamide (0.3 ml.)and acetonitrile (0.75 ml.), and the mixture is treated with acetylchloride (60 mg.) and anhydrous stannous chloride (38 mg.) with stirringat 0° C. for 1 hour. The mixture is then allowed to warm up to roomtemperature and allowed to stir for a further 1 hour. The mixture isconcentrated under reduced pressure and then diluted with ethyl acetate.The organic solution is washed with water and aqueous sodium bicarbonateand finally dried (MgSO₄). Evaporation under reduced pressure gives anoil which was purified by preparative thin layer chromatography (silica,ethyl acetate-light petroleum ether, 3:2) to give the required productas a pale yellow foam (60 mg.).

NMR (CDCl₃): δ = 7.4(s) 5H; 7.2(d) 1H; 5.8(m) 4H; 5.3(d) 1H; 5.2(d) 1H;4.5(q) 2H; 4.0(s) 3H; 3.8(s) 2H; 3.6(s) 3H and 1.5(s) 9H.

d.7-d-(α-amino-α-phenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl-4-(tetrazol-5-yl)-Δ³-cephem trifluoroacetate

7-[D-(α-t-butoxycarbonylamino-α-phenyl)acetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-4-(methoxymethyltetrazol-5-yl)-Δ³-cephem (55 mg.) in trifluoroacetic acid (2 ml.) and anisole (0.5 ml.)is allowed to stand at 20° C. for 6 hrs. The trifluoroacetic acid isevaporated under reduced pressure and the residue treated with ether.The solid which results is collected and washed with portions of dryether. The solid is dried under high vacuum to give the desired productas the trifluoroacetic acid salt.

NMR (D₂ O/DMSOd₆ /trifluoroacetic acid-d): δ = 7.4(s) 5H; 5.8(d) 1H;5.2(d) 1H; 5.1(s) 1H; 4.2(s) 2H; 4.0(s) 3H and 3.6(s) 2H.

EXAMPLE 82

The procedure of Example 81A-D is repeated, starting with theappropriately substituted N-t-butoxycarbonylphenylglycine and requisitemethoxymethyl substituted Δ² -cephems of Examples 73 and 74, to providethe following products:

    ______________________________________                                         ##STR77##                                                                    Ar           *(configuration)                                                                              A                                                ______________________________________                                        3-HOC.sub.6 H.sub.4                                                                        D              H                                                 3,4-(HO).sub.2 C.sub.6 H.sub.3                                                             DL             H                                                 4-(CH.sub.3 O)C.sub.6 H.sub.4                                                              D              H                                                 4-HOC.sub.6 H.sub.4                                                                        L              H                                                 2-thienyl    D              H                                                 3-Cl4-HOC.sub.6 H.sub.4                                                                    D              H                                                 4-ClC.sub.6 H.sub.4                                                                        DL             C.sub.2 H.sub.3 N.sub.4 S*                        3-ClC.sub.6 H.sub.4                                                                        DL             C.sub.2 H.sub.3 N.sub.4 S*                        4-FC.sub.6 H.sub.4                                                                         D              C.sub.2 H.sub.3 N.sub.4 S*                        2-Br5-HOC.sub.6 H.sub.3                                                                    DL             C.sub.2 H.sub.3 N.sub.4 S*                        3-FC.sub.6 H.sub.4                                                                         D              C.sub.2 H.sub.3 N.sub.4 S*                        4-FC.sub.6 H.sub.4                                                                         L              C.sub.2 H.sub.3 N.sub.4 S*                        2-ClC.sub.6 H.sub.4                                                                        D              C.sub.2 H.sub.3 N.sub.4 S*                        2-ClC.sub.6 H.sub.4                                                                        L              C.sub.2 H.sub.3 N.sub.4 S*                        3-BrC.sub.6 H.sub.4                                                                        D              C.sub.2 H.sub.3 N.sub.4 S*                        3-BrC.sub.6 H.sub.4                                                                        L              C.sub.2 H.sub.3 N.sub.4 S*                        3-ClC.sub.6 H.sub.4                                                                        D              C.sub.2 H.sub.3 N.sub.4 S*                        4-ClC.sub.6 H.sub.4                                                                        D              C.sub.2 H.sub.3 N.sub.4 S*                        2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               DL             C.sub.2 H.sub.3 N.sub.4 S*                        3,4-Cl.sub.2 C.sub.6 H.sub.3                                                               DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             2-FC.sub.6 H.sub.4                                                                         D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-FC.sub.6 H.sub.4                                                                         D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-FC.sub.6 H.sub.4                                                                         L              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             4-BrC.sub.6 H.sub.4                                                                        D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-HOC.sub.6 H.sub.4                                                                        L              C.sub.3 H.sub.3 N.sub.2 S.sub.2 .sup.+            4-HOC.sub.6 H.sub.4                                                                        DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-CH.sub.3 C.sub.6 H.sub.4                                                                 D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-CH.sub.3 C.sub.6 H.sub.4                                                                 L              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             2-CH.sub.3 OC.sub.6 H.sub.4                                                                DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                     DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                     D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-thienyl-   D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-thienyl-   DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             4-CH.sub.3 C.sub.6 H.sub.4                                                                 D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-CH.sub.3 C.sub.6 H.sub.4                                                                 D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             3-Cl4-CH.sub.3 C.sub.6 H.sub.3                                                             D              C.sub.3 H.sub.3 N.sub.2 S.sub.2 .sup.+            3-Cl5-(CH.sub.3 O)C.sub.6 H.sub.3                                                          D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             2-Cl4-CH.sub.3 C.sub.6 H.sub.3                                                             DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             2-F3-CH.sub.3 C.sub.6 H.sub.3                                                              D              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             2-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                      DL             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+             ______________________________________                                         ##STR78##                                                                     ##STR79##                                                                

Starting with the Δ³ -cephem products of Examples 54 through 56 and theappropriately substituted phenylmalonic acid, and employing theprocedure of Example 27, the sodium salts of the following compounds areprepared:

    ______________________________________                                         ##STR80##                                                                            Ar               A                                                    ______________________________________                                        2-ClC.sub.6 H.sub.4   CH.sub.3 CO.sub.2                                       4-ClC.sub.6 H.sub.4   CH.sub.3 CO.sub.2                                       3-BrC.sub.6 H.sub.4   CH.sub.3 CO.sub.2                                       2-FC.sub.6 H.sub.4    CH.sub.3 CO.sub.2                                       4-FC.sub.6 H.sub.4    C.sub.2 H.sub.3 N.sub.4 S*                              4-CH.sub.3 OC.sub.6 H.sub.4                                                                         C.sub.2 H.sub.3 N.sub.4 S*                              2-CH.sub.3 C.sub.6 H.sub.4                                                                          C.sub.2 H.sub.3 N.sub.4 S*                              4-CH.sub.3 C.sub.6 H.sub.4                                                                          C.sub.2 H.sub.3 N.sub.4 S*                              4-HOC.sub.6 H.sub.4   C.sub.2 H.sub.3 N.sub.4 S*                              4-H.sub.2 NC.sub.6 H.sub.4                                                                          C.sub.2 H.sub.3 N.sub.4 S*                              2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                        CH.sub.3 CO.sub.2                                       3,4-F.sub.2 C.sub.6 H.sub. 3                                                                        CH.sub.3 CO.sub.2                                       3-F4-BrC.sub.6 H.sub.3                                                                              CH.sub.3 CO.sub.2                                       3-Cl4-HOC.sub.6 H.sub.3                                                                             CH.sub.3 CO.sub.2                                       3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                              C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+                   3-F4-CH.sub.3 OC.sub.6 H.sub.4                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+                   3-Cl4-H.sub.2 NC.sub.6 H.sub.3                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+                   3-thienyl-            C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+                   3-thienyl-            CH.sub.3 CO.sub.2                                       2-CH.sub.3 C.sub.6 H.sub.4                                                                          CH.sub.3 CO.sub.2                                       4-CH.sub.3 OC.sub.6 H.sub.4                                                                         CH.sub.3 CO.sub.2                                       ______________________________________                                         ##STR81##                                                                     ##STR82##                                                                

Employing the procedure of Example 77A-C, and starting with theappropriate alkanoyloxymethyl and 1-(alkanoyloxy)ethyl substituted Δ²-cephems of Examples 74 through 76, and the appropriate acids thefollowing products are prepared:

    __________________________________________________________________________     ##STR83##                                                                    Ar           Q  n  R.sub.1     H                                              __________________________________________________________________________    C.sub.6 H.sub.5                                                                            -- 0  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              2-ClC.sub.6 H.sub.4                                                                        -- 0  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              4-ClC.sub.6 H.sub.4                                                                        -- 0  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              2,3-Cl.sub.2 C.sub.6 H.sub.3                                                               -- 0  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              3,4-Cl.sub.2 C.sub.6 H.sub.3                                                               -- 0  CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                            H                                              3-FC.sub.6 H.sub. 4                                                                        -- 0  CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                            H                                              4-FC.sub.6 H.sub.4                                                                         -- 0  CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                            H                                              3,5-F.sub.2 C.sub.6 H.sub.3                                                                -- 0  CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                            H                                              4-BrC.sub.6 H.sub.4                                                                        -- 0  (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                       C.sub.2 H.sub.3 N.sub.4 S*                     3,4-Br.sub.2 C.sub.6 H.sub.3                                                               -- 0  (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                       C.sub.2 H.sub.3 N.sub.4 S*                     3-HOC.sub.6 H.sub.4                                                                        -- 0  (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                       C.sub.2 H.sub.3 N.sub.4 S*                     4-HOC.sub.6 H.sub.4                                                                        -- 0  (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                       C.sub.2 H.sub.3 N.sub.4 S*                     4-CH.sub.3 C.sub.6 H.sub.4                                                                 -- 0  CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                               C.sub.2 H.sub.3 N.sub.4 S*                     3-Cl4-HOC.sub.6 H.sub.3                                                                    -- 0  CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                               C.sub.2 H.sub.3 N.sub.4 S*                     3-F4-HOC.sub.6 H.sub.3                                                                     -- 0  CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          4-CH.sub.3 OC.sub.6 H.sub.4                                                                -- 0  CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-Br4-CH.sub.3 OC.sub.6 H.sub.4                                                            -- 0  CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-CH.sub.34-HOC.sub.6 H.sub.3                                                              -- 0  CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-CH.sub.34-ClC.sub.6 H.sub.4                                                              -- 0  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          2-thienyl-   -- 0  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-thienyl-   -- 0  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              2-ClC.sub.6 H.sub.4                                                                        N.sub.3                                                                          1  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              4-ClC.sub.6 H.sub.4                                                                        N.sub.3                                                                          1  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              2,4-Cl.sub.2 C.sub.6 H.sub.3                                                               N.sub.3                                                                          1  CH.sub.3 CO.sub.2 CH.sub.2                                                                H                                              4-FC.sub.6 H.sub.4                                                                         N.sub.3                                                                          1  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         H                                              3,5-F.sub.2 C.sub.6 H.sub.3                                                                N.sub.3                                                                          1  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         H                                              4-BrC.sub.6 H.sub.4                                                                        N.sub.3                                                                          1  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         H                                              4-HOC.sub.6 H.sub.4                                                                        N.sub.3                                                                          1  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         C.sub.2 H.sub.3 N.sub.4 S*                     3-HOC.sub.6 H.sub.4                                                                        N.sub.3                                                                          1  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         C.sub.2 H.sub.3 N.sub.4 S*                     4-CH.sub.3 OC.sub.6 H.sub.4                                                                N.sub.3                                                                          1  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         C.sub.2 H.sub.3 N.sub.4 S*                     3-F4-HOC.sub.6 H.sub.3                                                                     N.sub.3                                                                          1  C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                         C.sub.2 H.sub.3 N.sub.4 S*                     3-Cl4-HOC.sub.6 H.sub.3                                                                    N.sub.3                                                                          1  C.sub.8 H.sub.5 O.sup.#                                                                   C.sub.2 H.sub.3 N.sub.4 S*                     3-Br4-CH.sub.3 OC.sub.6 H.sub.3                                                            N.sub.3                                                                          1  C.sub.8 H.sub.5 O.sup.#                                                                   C.sub.2 H.sub.3 N.sub.4 S*                     4-CH.sub.3 C.sub.6 H.sub.4                                                                 N.sub.3                                                                          1  C.sub.8 H.sub.5 O.sup.#                                                                   C.sub.2 H.sub.3 N.sub.4 S*                     3-Cl4-CH.sub.3 C.sub.6 H.sub.3                                                             N.sub.3                                                                          1  C.sub.8 H.sub.5 O.sup.#                                                                   C.sub.2 H.sub.3 N.sub.4 S*                     4-CH.sub.3 C.sub.6 H.sub.4                                                                 N.sub.3                                                                          1  C.sub.8 H.sub.5 O.sup.#                                                                   C.sub.2 H.sub.3 N.sub.4 S*                     3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                      N.sub.3                                                                          1  C.sub.8 H.sub.5 O.sup.#                                                                   C.sub.2 H.sub.3 N.sub.4 S*                     2-thienyl-   N.sub.3                                                                          1  CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                               C.sub.2 H.sub.3 N.sub.4 S*                     3-thienyl    N.sub.3                                                                          1  C.sub.8 H.sub.5 O.sup.#                                                                   H                                              __________________________________________________________________________     ##STR84##                                                                     ##STR85##                                                                     ##STR86##                                                                

Again, employing the alkanoyloxymethyl and 1-(alkanoyloxy)ethyl cephemsof Examples 74-76 and the appropriate acids, and utilizing the procedureof Example 79-A-C, the following compounds are prepared:

    __________________________________________________________________________     ##STR87##                                                                    Ar          *(configuration)                                                                      R.sub.1    A                                              __________________________________________________________________________    2-ClC.sub.6 H.sub.4                                                                       D       CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              3-ClC.sub.6 H.sub.4                                                                       D       CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              4-ClC.sub.6 H.sub.4                                                                       DL      CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              2-FC.sub.6 H.sub.4                                                                        L       CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              4-FC.sub.6 H.sub.4                                                                        D       CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              4-FC.sub.6 H.sub.4                                                                        L       C.sub.8 H.sub.5 O.sup.#                                                                  H                                              3-BrC.sub.6 H.sub.4                                                                       DL      C.sub.8 H.sub.5 O.sup.#                                                                  H                                              3-CH.sub.3 C.sub.6 H.sub.4                                                                D       C.sub.8 H.sub.5 O.sup.#                                                                  H                                              4-CH.sub.3 C.sub.6 H.sub.4                                                                DL      C.sub.8 H.sub.5 O.sup.#                                                                  H                                              4-CH.sub.3 OC.sub.6 H.sub.4                                                               D       C.sub.8 H.sub.5 O.sup.#                                                                  C.sub.2 H.sub.3 N.sub.4 S*                     4-CH.sub.3 OC.sub.6 H.sub.4                                                               DL      C.sub.8 H.sub.5 O.sup.#                                                                  C.sub.2 H.sub.3 N.sub.4 S*                     3-CH.sub.3 OC.sub.6 H.sub.4                                                               D       (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     2-HOC.sub.6 H.sub.4                                                                       D       (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     3-HOC.sub.6 H.sub.4                                                                       D       (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     4-HOC.sub.6 H.sub.4                                                                       DL      (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     4-HOC.sub.6 H.sub.4                                                                       D       (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub. 3 N.sub.4 S*                    2-CH.sub.3 C.sub.6 H.sub.4                                                                D       C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                                                    C.sub.2 H.sub.3 N.sub.4 S*                     2,4-Cl.sub.2 C.sub.6 H.sub.3                                                              D       C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                                                    C.sub.2 H.sub.3 N.sub.4 S*                     2,3-Cl.sub.2 C.sub.6 H.sub.3                                                              DL      C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                                                    C.sub.2 H.sub.3 N.sub.4 S*                     3,5-Cl.sub.2 C.sub.6 H.sub.3                                                              D       C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                                                    C.sub.2 H.sub.3 N.sub.4 S*                     2-Cl4-FC.sub.6 H.sub.3                                                                    D       CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-Cl4-FC.sub.6 H.sub.3                                                                    DL      CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-Cl4-BrC.sub.6 H.sub.3                                                                   L       CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3,4-Br.sub.2 C.sub.6 H.sub.3                                                              D       CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-F4-CH.sub.3 C.sub.6 H.sub.3                                                             DL      CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                     D       CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                           C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3,4-(HO).sub.2 C.sub.6 H.sub.3                                                            D       CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                           C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-Cl4-HOC.sub.6 H.sub.3                                                                   L       CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                           H                                              2-F4-HOC.sub.6 H.sub.3                                                                    DL      CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                           H                                              2-F4-CH.sub.3 OC.sub.6 H.sub.3                                                            DL      CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                           H                                              3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                    D       CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              3-CH.sub.3 O4-HOC.sub.6 H.sub.3                                                           D       CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.4 S*                     3-Br5-HOC.sub.6 H.sub.3                                                                   L       CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.4 S*                     3-CH.sub.34-HOC.sub.6 H.sub.3                                                             D       CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.4 S*                     3-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                     DL      (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     3-CH.sub.34-BrC.sub.6 H.sub.3                                                             D       (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     __________________________________________________________________________     ##STR88##                                                                     ##STR89##                                                                     ##STR90##                                                                

Utilizing the procedure of Example 81A-C, and starting with thealkanoyloxymethyl and 1-(alkanoyloxy)ethyl Δ² -cephems of Examples 74-76and the appropriately substituted N-t-butoxycarbonylphenylglycine, thefollowing products are prepared:

    __________________________________________________________________________     ##STR91##                                                                    Ar         *(configuration)                                                                       R.sub.1    A                                              __________________________________________________________________________    3-HOC.sub.6 H.sub.4                                                                      D        CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              3,4-(HO).sub.2 C.sub.6 H.sub.3                                                           DL       CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              4-(CH.sub.3 O)C.sub.6 H.sub.4                                                            D        CH.sub.3 CO.sub.2 CH.sub.2                                                               H                                              4-HOC.sub.6 H.sub.4                                                                      L        CH.sub.3 CO.sub.2 CH                                                                     H                                              2-thienyl- D        CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              3-Cl4-HOC.sub.6 H.sub.3                                                                  D        CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              4-ClC.sub.6 H.sub.4                                                                      DL       CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              C.sub.2 H.sub.3 N.sub.4 S*                     3-ClC.sub.6 H.sub.4                                                                      DL       CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              C.sub.2 H.sub.3 N.sub.4 S*                     4-FC.sub.6 H.sub.4                                                                       D        CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              C.sub.2 H.sub.3 N.sub.4 S*                     2-Br5-HOC.sub.6 H.sub.3                                                                  DL       (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     3-FC.sub.6 H.sub.4                                                                       D        (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     4-FC.sub.6 H.sub.4                                                                       L        (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     2-ClC.sub.6 H.sub.4                                                                      D        (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     2-ClC.sub.6 H.sub.4                                                                      L        (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     3-BrC.sub.6 H.sub.4                                                                      D        (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                      C.sub.2 H.sub.3 N.sub.4 S*                     3-BrC.sub.6 H.sub.4                                                                      L        CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-ClC.sub.6 H.sub.4                                                                      D        CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          4-ClC.sub.6 H.sub.4                                                                      D        CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          2,4-Cl.sub.2 C.sub.6 H.sub.3                                                             DL       CH.sub.3 CO.sub.2 CH.sub.2                                                               C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3,4-Cl.sub.2 C.sub.6 H.sub.3                                                             DL       C.sub.8 H.sub.5 O.sup.#                                                                  C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          2-FC.sub.6 H.sub.4                                                                       D        C.sub.8 H.sub.5 O.sup.#                                                                  C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-FC.sub.6 H.sub.4                                                                       D        C.sub.8 H.sub.5 O.sup.#                                                                  C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+          3-FC.sub.6 H.sub.4                                                                       L        C.sub.8 H.sub.5 O.sup.#                                                                  H                                              4-BrC.sub.6 H.sub.4                                                                      D        C.sub.8 H.sub.5 O                                                                        H                                              3-HOC.sub.6 H.sub.4                                                                      L        C.sub.8 H.sub.5 O                                                                        H                                              4-HOC.sub.6 H.sub.4                                                                      DL       CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              3-CH.sub.3 C.sub.6 H.sub.4                                                               D        CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              3-CH.sub.3 C.sub.6 H.sub.4                                                               L        CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              2-CH.sub.3 OC.sub.6 H.sub.4                                                              DL       CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                   DL       CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                   D        CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              H                                              3-thienyl- D        CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                              C.sub.2 H.sub.3 N.sub.4 S*                     3-thienyl- DL       (CH.sub.2).sub.2 CHCO.sub.2 CH.sub.2                                                     C.sub.2 H.sub.3 N.sub.4 S*                     4-CH.sub.3 C.sub.6 H.sub.4                                                               D        (CH.sub. 2).sub.2 CHCO.sub.2 CH.sub.2                                                    C.sub.2 H.sub.3 N.sub.4 S*                     3-CH.sub.3 C.sub.6 H.sub.4                                                               D        (CH.sub.2).sub.2 CHCO.sub.2 CH.sub.2                                                     C.sub.2 H.sub.3 N.sub.4 S*                     3-Cl4-CH.sub.3 C.sub.6 H.sub.3                                                           D        (CH.sub.2).sub.2 CHCO.sub.2 CH.sub.2                                                     C.sub.2 H.sub.3 N.sub.4 S*                     3-Cl5-(CH.sub.3 O)C.sub.6 H.sub.3                                                        D        (CH.sub.2).sub.2 CHCO.sub.2 CH.sub.2                                                     C.sub.2 H.sub.3 N.sub.4 S*                     2-Cl4-CH.sub.3 C.sub.6 H.sub.3                                                           DL       (CH.sub.2).sub.2 CHCO.sub.2 CH.sub.2                                                     C.sub.2 H.sub.3 N.sub.4 S*                     2-F3-CH.sub.3 C.sub.6 H.sub.3                                                            D        CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                           C.sub.2 H.sub.3 N.sub.4 S*                     2-CH.sub.34-CH.sub.3 OC.sub.6 H.sub.3                                                    DL       CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                           C.sub.2 H.sub.3 N.sub.4 S*                     __________________________________________________________________________     ##STR92##                                                                     ##STR93##                                                                     ##STR94##                                                                

The procedure of Example 77-A-C is repeated, starting with the requisiteacid and alkanoyloxymethyl and 1-(alkanoyloxy)ethyl Δ² -cephems ofExamples 74-76, to give the following congeners:

    ______________________________________                                         ##STR95##                                                                    Ar      n     R.sub.1           A                                             ______________________________________                                        C.sub.6 H.sub.5 O                                                                     1     CH.sub.3 CO.sub.2 C.sub.2                                                                       H                                             C.sub.6 H.sub.5 O                                                                     1     CH.sub.3 (CH.sub.2).sub.3 CO.sub.2 CH.sub.2                                                     H                                             C.sub.6 H.sub.5 O                                                                     1     CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                                  H                                             C.sub.6 H.sub.5 O                                                                     1     (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                             H                                             4-C.sub.5 H.sub.4 S                                                                   1     CH.sub.3 CO.sub.2 CH.sub.2                                                                      H                                             4-C.sub.5 H.sub.4 S                                                                   1     C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                               H                                             4-C.sub.5 H.sub.4 S                                                                   1     C.sub.2 H.sub.5 CO.sub.2 CH.sub.2                                                               C.sub.2 H.sub.3 N.sub.4 S*                    4-C.sub.5 H.sub.4 S                                                                   1     (CH.sub.3).sub.2 CHCO.sub.2 CH.sub.2                                                            C.sub.2 H.sub.3 N.sub.4 S*                    4-C.sub.5 H.sub.4 S                                                                   1     CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                                  C.sub.2 H.sub.3 N.sub.4 S*                    C.sub.6 H.sub.5 S                                                                     1     CH.sub.3 CO.sub.2 CH(CH.sub.3)                                                                  C.sub.2 H.sub.3 N.sub.4 S*                    C.sub.6 H.sub.5 S                                                                     1     (CH.sub.3).sub.2 CHCH.sub.2 CO.sub.2 CH.sub.2                                                   C.sub.2 H.sub.3 N.sub.4 S*                    C.sub.6 H.sub.5 S                                                                     1     CH.sub.3 (CH.sub.2).sub.2 CO.sub.2 CH.sub.2                                                     C.sub.2 H.sub.3 N.sub.4 S*                    C.sub.6 H.sub.5 S                                                                     1     C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                                                           C.sub.2 H.sub.3 N.sub.4 S*                    C.sub.6 H.sub.5 S                                                                     1     C.sub.2 H.sub.5 CO.sub.2 CH(CH.sub.3)                                                           C.sub.3 H.sub.3 N.sub.2 S.sub.2 .sup. +       C.sub.6 H.sub.5 S                                                                     1     (CH.sub.3).sub.3 CCO.sub.2 CH.sub.2                                                             C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         2-C.sub.4 H.sub.3 S                                                                   0     CH.sub.3 CO.sub.2 CH.sub.2                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         2-C.sub.4 H.sub.3 S                                                                   1     CH.sub.3 CO.sub.2 CH.sub.2                                                                      C.sub.3 H.sub.3 N.sub.2 S.sub.2.sup.+         C.sub.6 H.sub.5 O                                                                     1     C.sub.8 H.sub.5 O.sup.#                                                                         H                                             C.sub.6 H.sub.5 S                                                                     1     C.sub.8 H.sub.5 O.sup.#                                                                         H                                             CN      1     CH.sub.3 CO.sub.2 CH.sub.2                                                                      H                                             Br      1     CH.sub.3 (CH.sub.2).sub.2 CO.sub.2 CH.sub.2                                                     H                                             3-C.sub.4 H.sub.3 S                                                                   0     CH.sub.3 CO.sub.2 CH.sub.2                                                                      H                                             3-C.sub.4 H.sub.3 S                                                                   1     CH.sub.3 CO.sub.2 CH.sub.2                                                                      H                                             ______________________________________                                         ##STR96##                                                                     ##STR97##                                                                     ##STR98##                                                                    ______________________________________                                    

EXAMPLE 88

The following ingredients are blended together in the indicatedproportions by weight.

    ______________________________________                                        Sucrose, U.S.P.        80.0                                                   Tapioca Starch         13.5                                                   Magnesium stearate     6.5                                                    7-Phenylacetamido-3-methyl-4-                                                                        100.0                                                  (tetrazol-5-yl)-Δ.sup.3 -cephem                                         ______________________________________                                    

After the composition is thoroughly blended, tablets are punched fromthe mixture, each tablet being of such size as to contain 100 mg. of thecephem compound.

Tablets are also prepared containing respectively 50 and 250 mg. ofactive ingredient, by selecting the appropriate proportions of cephemcompound and excipient blend in each case.

EXAMPLE 89

The following ingredients are blended together in the indicatedproportions by weight.

    ______________________________________                                        Calcium carbonate      17.6                                                   Dicalcium phosphate    18.8                                                   Magnesium trisilicate  5.2                                                    Lactose, U.S.P.        5.2                                                    Potato starch          0.8                                                    7-Phenoxyacetamido-3-methyl-                                                                         50.0                                                   4-(tetrazol-5-yl)-Δ.sup.3 -cephem                                       ______________________________________                                    

The thoroughly-mixed pharmaceutical composition is filled into softgelatin capsules, such that each capsule contains 100 mg. of activeingredient.

Capsules are also prepared containing respectively 50 and 250 mg. ofactive ingredient by varying the proportions of cephem compound andexcipient blend.

EXAMPLE 90

The sodium salt of 7-(2-thienylacetamido)-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem is thoroughly mixed and ground with sodium citrate (4% byweight). The ground, dry mixture is sterilized and packed into sterilevials, which are then stoppered with serum caps under sterileconditions. When it is intended to use this preparation, sufficientsterile water is injected into the vials to dissolve the contents, andgive a solution containing 25 mg./ml. of active ingredient. Forparenteral use, the solution is withdrawn from the vials using ahypodermic syringe.

In a similar manner, by varying the amount of water added, solutionscontaining respectively 10, 50, 100 and 200 mg./ml. of active ingredientare prepared.

EXAMPLE 917-[D-(α-Amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem Potassium Salt

To a stirred solution of 1.94 g.7-[D-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem in 100 ml. of methanol, cooled to -30° C., is added dropwisesufficient 1.0N solution of potassium hydroxide in methanol such thatone equivalent of base is added. The mixture is allowed to warm to 0°C., and then it is added dropwise with stirring to 700 ml. of ether. Thesolid which precipitates is removed by filtration and dried under highvacuum. This affords the title potassium salt in good yield.

When the above procedure is repeated, except that the potassiumhydroxide used therein is replaced by an equimolar amount of sodiumhydroxide, the product is the sodium salt of7-[D-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem.

EXAMPLE 927-[D-α-Amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem Calcium Salt

To a stirred solution of 3.87 g. of7-[D-α-amino-α-(p-hydroxyphenyl)-acetamido]-3-methyl-4-(tetrazol-5-yl)-Δ³-cephem in 40 ml. of dimethylformamide is added a turbid solution of 370mg. of calcium hydroxide over 5 minutes. The mixture is heated at35°-40° C. for 1 hour, and then an additional 30 ml. ofdimethylformamide is added. Heating at 35°-40° C. is continued for afurther 30 minutes, and then the cooled solution is added dropwise to700 ml. of ether. An oil precipitates. The solvent is decanted off andto the residue is added 100 ml. of ethanol, followed by 400 ml. ofether. The oil slowly solidifies and then it is recovered by filtrationand dried under high vacuum. This affords the title calcium salt.

EXAMPLE 937-[D-(α-Amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem Hydrochloride Salt

A slurry of 50 mg. of7-[D-(α-amino-α-phenyl)acetamido]-3-methyl-4-(tetrazol-5-yl)-.DELTA.³-cephem in 2 -ml. of de-ionized water is stirred for 5 minutes atambient temperature. The pH is then adjusted to 2.45 using dilutehydrochloric acid, and the solution thus obtained is immediatelylyophilized. This affords the hydrochloride salt of the desiredcompound, a white solid.

What is claimed is:
 1. A compound selected from the group consisting of##STR99## wherein R is selected from the group consisting of2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl andbenzyloxycarbonyl.R₁ is selected from the group consisting of hydrogen,alkanoyloxy-methyl having from three to six carbon atoms,1-(alkanoyloxy)ethyl having from four to seven carbon atoms,methoxymethyl, and phthalidyl; and R₁₁ is selected from the groupconsisting of hydrogen, alkanoyloxymethyl having from three to sixcarbon atoms, 1-(alkanoyloxy)ethyl having from four to seven carbonatoms, methoxymethyl, phthalidyl, ##STR100## wherein R₆ is selected fromthe group consisting of alkyl having from one to three carbon atoms andphenyl and R₇ is selected from the group consisting of hydroxy, methoxy,alkanoyloxy having two to four carbon atoms, and benzyloxy and R₈ isselected from the group consisting of hydrogen, hydroxy, fluoro, chloro,bromo, iodo, methyl, methoxy, alkanoyloxy having from two to four carbonatoms, phenyl and benzyloxy and ##STR101## wherein R₉ and R₁₀ are eachselected from the group consisting of hydrogen and methyl and X isselected from the group consisting of oxygen and sulfur.
 2. A compoundof claim 1 wherein R is 2,2,2-trichloroethoxycarbonyl.
 3. The compoundof claim 27-(2',2',2'-trichloroethoxycarboxamido)-3-bromomethyl-4-[1-methoxymethyl)tetrazol-5-yl]-Δ²-cephem.
 4. The compound of claim 2,7-(2',2',2'-trichloroethoxycarboxamido)-3-bromomethyl-4-[2-(methoxymethyl)tetrazol-5-yl]-Δ²-cephem.